428 Pfejcripf on Accejsor e* end Reloled I*®™*
Fio 146 (Top) Qasljc hose Left to
fight oserknee Ightweght two-way
stretch full fool seamless nylon clastic
hose s milar with partial foot only siroi
lar underknee (garter) length surgical
weight oneway stretch garter length
rayon and cotton hose (Bottom) E*
iremity supports Left to nght knee sup-
port ankle support and wnst support
couraged at least to wear a heavier stocking
while at home
Both forms of stocking are available i**
lengths ranging from below knee or gartc^
styles to thigh hose and consideration niu^t
be gisen as to where the support is needc**
(Fig 146 lop) Some hate a full foot bu*
more often the toe and sometimes the he^^
arc cut out so that a pair of dress hose may b®
worn over them Seamless hose is popular
because it is more easily covered
0astic hose is put on by rolling or folding
It down until the foot may be mserted easily
into the toe end and then rolling it back up
the leg with a minimum of tugging and pull
mg &mc wearers in order to prevent swell
mg need to put on the hose before arising
Proper care of the clastic stocking is im
portant since the rubber m it is subject to
dctenoration from oils heat and other cnvi
ronmental factors mentioned previously
Daily washing with soap and water, adequate
rmsmg and drying and a resting penod be
tween weanngs are desirable for maximum
‘iftc Honsequctifiy fne user Snoiiici ‘nave at
least two stockmgs for each afTected leg
Cxlremily Supports Anklets knee caps
and elbow braces arc made of rubber thread
covered with cotton and woven into seamless
surgical weight lubes shaped appropnately to
fit the areas which each is intended to sup'
port (Fig 146 botiom) They arc used most
often to compress support and immobilize
sprains or wrenched joints Sizes run from
small to extra large with fitting done by
having the client try on the support Hinged
knee caps with jointed steel side bars are
ava hblc to supply lateral support when
needed for severe sprains Wnstlets (Fig
146 botiom) also arc used to support a weak
wrist and arc available m leather as well as
m clastic cloth Leather wristbands have one
to three straps depending on their width and
may be lined or unlincd Elastic and leather
wristlets often are made in a smgle size which
IS adjusted to fit the wnst through snap
buttons or buckles
Suspensories arc used for a wide vanety
of conditions involving the scrotum and its
contenu Conservative treatment of vanco
celc cpididyanius and orchitis calls for wear
mg a suspensory They arc also used to
support the scrotum after treatment of hydro-
cele and after hernia repair prostatectomy
and scrotal surgery In each instance the
(unction of the suspensory is to hold up or
to support the scrotum so as to relieve the
pam and discomfort attendant on the afllic
tioos listed above
Suspensories consist of a pouch attached
to a body belt (Fig 147, leji) Some also
Prescription Pharmacy
Copyright © 1963, by J B Lippiscott Company
This book ]S fully protected by copyright and, with the excepUoo
of bnef extracts for review, no part of it may be reproduced
m any form without the written pennission of the publisher
The use of portions of the text of the United States Pharmacopeia, Sixteenth Revision, official
October 1, 1960, is by permission received from the Board of Trustees of the Umted States
Pharmacopcial Convention The said Board is not responsible for inaccuracies of the text
thus used.
Permission to use portions of the text of the Nationai Formulary, Eleventh Edition, official
October 1, 1960, has been granted by the American Pharmaceutical Association, The
American Pharmaceuucal Association is not responsible for any maccuracy of quotation,
or for false implications that may arise by reason of the separation of excerpts from the
original context.
Distributed in Great Bntam by
Pitman Medical Publishing Co , Limited, London
Library of Congress Catalog Card Number 63 20825
Printed m the United States of America
Preface
Rapid progress m the art of therapeutics
has brought Carnatic changes m the practice
of pharmacy No longer is the dispensmg of
prescnpUons a test of the pharmacist’s com-
pounding skills, ra±er, it is a challenge to
his knowledge of dosage forms and his abihty
to mterpret this knowledge for the best m-
terests of the patient and the physician whom
he serves
Teachers of dispensmg pharmacy have
recognized the nature of t^ change and
have felt the need for a text which can serve
as a gui^ for the type ot mstmction now re-
quired Pharmacists, too, are searchmg for
a text which presents, m an organized fash-
ion, essential facts relating to the properties
and the uses of modem pharmaceuticals
This book is mteoded to be a treatise which
deals with all aspects relatmg to the dispeos-
mg of dosage forms — their capabihties, ad-
vantages, duadvantages, compatibilities and
mcompaubilities It deals with methods for
their preparation because we cannot divorce
methods of preparation from the qualities
exhibited by dosage forms The organization
of the text follows a physicochemical classi-
fication. This system of study should be par-
ticularly useful to those who have received
previous instruction m physical pharmacy
The chapter on bYopharmateuUca is a par-
ticularly welcome action, smce it brmgs
together much of the information pertaining
to the relationship between physical charac-
teristics of pharmaceuticals and their biologic
activity Ihe chapter dealmg with radio-
phannaceuUcals is similarly umque m that it
contains much correlative material regardmg
potency and type of radiation and person^
safe^ of operators The subject of radiation
hygiene will command greater attention from
pharmacists m the future than has been the
case m the past
Sickroom supphes and apphances are
closely identified with prescriptions In some
cases, devices are limited to prescription sale
TheieiDie, ilis appropnale^at these be con-
sidered m a textbook dealmg with prescrip-
tion practice Similarly, it seems appropriate
to mclude information regarding the profes-
sionals whose orders axe fulfilled through
prescription service Thus, the text mcludes
not only prescnpiion pharma^ but closely
related topics as well
In today’s fast moving world, informa-
tion IS often superseded before it finds its
way mto print If such should happen in this
case, It will be due to the mevitable and m-
exorable advances of modem pharmaceutical
science The authors have made every effort
to interpret pharmaceutical practice m terms
of unchangmg physical and chemical prm-
ciples m order that the book may be useful,
even though the art contmues to change
The editor and the publisher wish to ex-
press appreciation to those pharmaceutical
educators who gave generous assistance m
the design and preparation of the text
Joseph B Sprowls
Contents
V>ll
4 Solution Dosage Forms {Continued)
Colormg and Flavonng 163
Packaging 165
Special Elutions 165
5 Liquid Dosage Forms Containing Insoluble Matter 178
Harold M Beal
Liquid Dosage Forms Containing Insoluble Mailer 173
Properties of Liquid Dosage Forms Containing Insoluble Matter 178
Particle Size m Relation to Pharmacologic Action 179
Solid In Liquid Dispersions (Suspensions) 180
Liquid'In Liquid Dispersions (Emulsions) 188
Packaging, Dispensing and Storage of Liquid Dosage Forms Containing
Insoluble Matter 199
6 Semisolid Dosage Forms 201
Seymour Blaug
ElTccts of Locally Applied Drugs 202
Classification of Omtmenis 203
General Indications for Omtmcnt Bases 204
Ejects of Vehicles on the Skin 204
Oleaginous Bases 209
Absorption Bases 212
Emulsion Bases 214
Water-Soluble Bases 216
Ophthalmic Ointments 217
Preparation of Ointments 218
Packaging. Storage and Labeling of Omtmenis 221
Other Topical Preparations 222
7 Suppositories
Charles F Peterson
Therapeutic Uses
Testing of the Suppository
Suppository Bases
Methods of Manufacture
Special Dispensing and Compounding Procedures for Suppositories
8 Aerosols
John! Sciarra
Introduction
Definitions
History
Pharmaceutical and Mcdicmal Aerosols
Mode of Operation of Aerosols
Manufacture of Aerosol Products
Physicochemical Properties of Propellants
Aerosol Containers
Aerosol Vaises
Pharmaceutical Aerosols
Medicinal Aerosols
Veterinary Aerosol Products
Special Tesung of Aerosols
226
228
229
230
235
238
241
241
242
243
245
246
253
256
273
273
277
283
285
286
Therapeutic Incompatibility 290
Physical Incompatibility 291
Chemical Incompatibility 291
lacompatibihlies of Inorgamc Compounds 292
10 Incompatibilities of Organic Compounds 305
DaleE Wurster
Hydrocarbons 3 Q 5
Alcohols 306
Phenols 310
Aldehydes 313
Ketones 316
Carboxylic Acids 317
Esters 324
Ethers 328
Basic Nitrogen-Contaimng Compounds 329
Acidic Nitrogen-Contaming Compounds 345
Dyes 351
Glycosides 363
Resms 364
Silver Protem Preparations 365
Antibiotics 365
11. Services to the Allied Professions 381
RoyC Darlington
Introduction 381
Medicine 382
Dentistry 383
Homeopathy 387
Osteopathy 389
Podiatry (Chiropody) 391
Vetermaiy Medicme 393
12 Prescription Accessories and Related Items 400
Waller Smger
Clmical Thermometers 400
Rubber and Plastic Accessones 407
Elastic Support Items 426
Sickroom Utensils 429
Electric Healmg Pads 430
Vaporizer-Humidifiers 432
Atomizers, Nebulizers, Insufflators 434
Hypodermic Syringes and Needles 440
Diabetic Supplies 448
Diabetic Unne Tests 449
Surgical Dressings and Related Supplies 450
Crutches and Canes 461
Infrared and Ultraviolet Generators 464
Contents
13 Hospital Pharmacy 47g
GcorgoF Aichambault
Histoiy 475
Amcncaa Society of Hospital Pharmacists 477
Vital Statistics on Hospital Pharmacy m the United States 478
Responsibilities and Duucs of the Hospital Pharmacist 478
Organization and Policies 480
The Hospital Formulary aoj
Personnel 435
Physical Facilities 486
Equipment 49O
Laws and Regulations 491
Invcsugational Drugs 500
Safety Practices 501
Volume Compounding 503
Prcpackagmg 504
Standardization of Prescription and Ward Issue Medication Containers 507
Inpatient Dispensmg 507
Labels and Contamers 507
House Requisitioning of Drugs 509
Inspection of Nursiog-Station Medication Umts 509
Outpauenl Department 511
Emergency and Antidotal Drugs Cabmet 511
Drug Charges S12
Purchasing 512
Central SterJe Supply 513
Management Respoosibiliucs 513
Inventory Policy — Stores 514
Storeroom Arrangement and Control of Stock 5 1 4
Perpetual layentory Records ' 515
A Quarterly and Annual Reporting System for Costs and Workloads 516
Automation 522
Residencies 523
14 Radiopharmaceuticals
William H Brmcr
History
Philosophy of Radiopharmaceutical Service
T^pcs of Radioactivity
Radioactive Decay
Units of Radioactivity
Radiation Protection
Calculations
Radiation DetccUoa Instruments
Other Equipment
Dosage Forms
Formulation and Dispensing Procedures
Uses of Radiophaimaccutical Products
Other Research Applications
Laws and Regulations Regarding Procurement and Use of Radionuclides
Summary
525
525
525
526
523
531
533
538
539
548
549
550
551
555
556
557
No EX
561
Prescription Pharmacy
The Prescripfion
Elmer M Hem, Ph D *
HISTORY OF THE PRESCRIPTION
Until comparatively recently, it commonly
was agreed Aat the art of prescription wnt-
mg originated m the distant past It was
thought that the Egyptian pnests practiced
prescnption writmg because they engaged in
treatmg the sick in addition to their religious
duties There are preserved in museums such
Egyptian records as those cut on stone or
written on papyrus which contain a vanety
of medical formulas There are several for-
mulas preserved m the British Museum which
are said to date from the tune of the Cheops,
about 3700 b c
The Ebers Papyrus, wntteo m about the
16th century b c , is considered to be an un-
official formulary or pnvate recipe book It
contains many mvocations for dnvmg away
disease and specific recipes directing the use
of drugs 10 common use today Some of the
formulas m the Ebers Papyrus tended toward
polypharmacy These recipes, callmg for as
many as 35 ingredients, were mtended to
treat the more complex illnesses Each for-
mula names the mgredients and the quan-
tities to be used and gives directions for the
preparation and the use of the medicines It
is bought possible that the preparation of
the medicine m a form to be used by the pa-
tient was accomplished by a class of mdi-
viduals correspondmg to today’s pharmacists
According to these ideas, the separation
of pbannacy and medicme as professions
could have originated a few thousand yean
ago However, the late Dr George Urdang,
who did considerable research on the history
of the prescription, claimed that there could
• Coordmator of Pbarmaceuucal Services Pro-
fessor of Pharmacy University of Washington.
not have been any prescriptions before about
AD 1000, if by prescnption” we under-
stand It to be a wntten order by a physician
to a pharmacist Dr Urdang pomted out that,
while It is true that these formulas have come
down to us from Assynan Babylonian and
Egyptian antiquity, the former wntten on
clay tablets and the latter on stone and pa-
pyrus, they are not prescnptions as such
TTiey are merely formulas or recipes to be
used as guides by those mixing medicmes
Nothmg is known about mdmdual prescrip-
tion filling dunng this period
Early pharmacy and medicine m Greece
were centered around the supernatural
Though sunple herb medicmes were used,
there was strong reliance on mcaotations and
prayen Creek physicians prepared their own
meffiemes, although a special class of mdi-
viduals, rhizotomoi, dug the medicmal plants
It was Hippocrates who was responsible
for Seeing medicme and surgety from the
supematurohstic basis Alexandnan conquest
of the Egyptians was responsible for the
Egyptian infiuence on Greek pharmacy and
meihcine The Greeks held strong contempt
for labor and the specialization of functions
was effected easily Even the surgeon was
placed outside the class m which the phy-
sician resided Perhaps the manual nature of
the duties of the rhizotomoi or the pharnia-
copofoi and the surgeon contributed U> the
rapid development of their skills
Greek culture, including medical theones
and practices, was passed on to the Romans
as a result of the Roman conquest of Greece
Thus, while early Roman formulas were those
built around mysticism, they soon became of
a rational, naturalistic nature
2 The Prescription
In Gracco-Roman uracs, according to Dr
Urdang, there were vanous groups of trades-
people who compounded medicines besides
mixing and selling perfumes, fumigations,
love potions, and fragrant oils and omtmcots
for athletes and gla^ators Howeser, those
people could not be classified as pharmacists
Dr Urdang also reminded us of the fact that
Pliny (23-79) and Galen (131-201) admon-
ished the physicians not to trust the pigmen-
tani (deders m d)estufls and medicmal
drugs) or the seplasam (importers of and
dealers m drugs and onental aromatics), but
to prepare the medicaments to be applied m
their practices themselves 'Ihcsc admoni-
tions prose that dispensing by the physician
was regarded as a mcdi^ ethical require-
ment, and that there had developed craftsmen
to whom at least some of the physicians dele-
gated the labonous task of nuxing mcdicmes
according to theu directions Nevertheless,
even m these cases the physician remomed
the one who applied the medicine or dis-
pensed the product for application to the
patient The present established circuit by
which the physician hands the patient a pre-
scription that IS brought to and filled by the
pharmacist, who in turn hands the finished
product to the patient, still did not exist as a
matter of routine
The history of pharmacy and medicine
smcc the tune of the great Roman Empuc is
not a story of steady advances The teachmgs
of such scicntifical/y minded men as Hip-
pocrates were replaced by magic and mys-
ticism during the period immediately before
the birth of Christianity Prescriptions in-
cluded amulets and charms to be worn by
the patient Certain words or phrases were
spoken dunng the preparation of the mcdi-
cme, and the patient was directed to face a
certam direction (usually the cast) when he
used the medicine
Throughout the Middle Ages, science rc-
mamed on a lower plane tlian that developed
by the Egyptians and the Greeks Mediae
dunng this period was largely in the hands
of pnests and monks, and ihcir religious be-
lief mfiucnced medical practice /Astrologers
and alchemists also mfiucnced prescnpuoo
wnting In their desire to hold the knowledge
of the practice of pharmacy and medicine
from the ^ncral populace, Ujcsc individuals
used symbols to mdicate the mcdicmal m-
grcdienis
It was the Arabians who preserved the art
of pharmacy and mcdicme They kept m close
contact with the classical tractions of the
Egyptians and the Greeks, and, after their
conquests m Europe, brought with them a
revival of learmng and science The Moham-
medan conquerors established on the Span-
ish penmsula such umvcrsiUcs as those of
Cordova, Murcia, Seville and Toledo From
these centers of learning, their mfiuencc
slowly made itself felt over the rest of Europe
Durmg the Middle Ages, the status of the
pharmacist was lowered because the physi-
cian tended to prepare his own medicines
Separation of pharmacy from medicine began
to be felt m Europe dunng the lltb century,
due to the influence of the Moors In the
Siatuta stve Leges of the southern French
town of Arles was a rule (supposed to have
origuutcd between 1162 and 1202) that the
pharmacist should accurately fill the pre-
senpuons of the physicians In this ordinance,
as well as in later similar ordinances, the
physician was obligated to observe the com-
pounding, or at least to be present until all
individual ingredients were collected, by the
phaimacist These reles provided restrictions
for both health professiW, forbidding the
phaimacist to counterpresenbe and the phy-
sician to dispense
In 1240, Frcdcnck II of Hohenstaufen
brought about legislation separating phar-
macy and mcdicme in the Two Sicilies From
the 13(h century on, phaimacists m some
European countries had to swear to fill con-
scientiously the presenpuons of the physi-
cians This oath is sull taken m some of those
couotnes Some time m the 14th ccntuiy,
specialization m the two professions began
to appear m England In 1683, the City
Council of Bruges, Belgium, passed a law
forbiddmg physicians to prepare their own
medicines Dr John Morgan, m America, in
1765 proposed the separauon of pharmacy
and rocdiane
Generally speaking, m Anglo-Saxon coua-
tnes the riglit of the physician to dispense
has been retained. In England, m 1911, the
mlroduction of compulsory health insurance
for employees withm certam income brackets
required prcscnpiions to be wniicn for tliosc
Flo I Typical prescription, properly wntten. See text for discussion of the various parts of
the prescription
people and hence lumted the right of the
physician to dispense Certain rules and legu*
lations (such as pension and ttorkmen s com-
pensation) in the United States also limit
the right of the physician to dispense under
certam conditions, though general/ hts right
to dispense is still unimpeded
DEFINITION OF PRESCRIPTION
A prescnption is an order for a medtcme
or medicines usually wntten as a formula by
a physician, a dentist, a vctermanaa or some
odier licensed medical practitioner It con-
tains the names and the quantities of the de-
sired substances, with instructions to the
pharmacist for the preparation of the medi-
cine and to the patient for the use of the
medicine at a particular tune
The prescnption may be (1) a formula
wntten on a piece of paper, usually a pre-
scription blank, or (2) it may be wntten by
the pbaimactst pursuant to the telephoned
dictation of the physician It may be (3 ) oral
instructions that direct the use of certam
drugs or call for the use of some physical
agent, such as heat. Therefore, oral presenp-
tioos may or may not concern the pharma-
cist. The term prescnption is extended also
to include (4) the finished product, that
drug or mixture of drugs compounded and
dispensed by the pharmacist pursuant to the
instructions of a presenber
PARTS OF THE PRESCRIPTION
Figure I represents a typical prescription
properly wntten on a printed blank of the
type often used m pharmacies for telephoned
prescnptions and for presenpuons which the
physician may wish to wnte when be is m
the pharma^ Along the side of the lUustra-
4 The Prescription
tion are numbers mdicating the various parts
of the prescnpiion
1 The name and the address of the pa<
ticnt usually are supplied by the presenber
If this mformation is laebng on the presenp-
tion, the pharmacist should add it to keep his
records complete Reasons for this are obvi-
ous Federal regulations require this informa-
tion on narcotic prescriptions The laws of
some states require the name of the patient
on all prescriptions
2 The date on nhich the prescription is
YiTitfcn usually is supplied by the prescribcr
According to Federal narcotic regulations,
narcotic-containmg prescriptions must be
dated The prescription illustrated in Figure 1
contains codeme sulfate and is subject to
control by Federal narcotic regulations
3 The supersenpUon is written I> and is
the s>mbol for the Latin word rcape ( take
thou,’ or ‘you take’), the imperative form
of the Latin verb recipn? I take ’
4 The inscription contains a list of the in-
gredients and their quantities to be used m
compounding the prescription
5 The subscription composes the direc-
tions to the pharmacist for the compounding
of the several ingredients into a form suitable
for use by the patient The class of the prep-
aration (capsule) IS noted and the number of
doscs(16) to be prepared is indicated
6 The tnmscnplion gives the necessary
directions to the patient for the use of the
prescnpiion ’(Take) two capsules every
four hours if needed ”
7 The name of the presenber may be
given as on olhcial signature which is re-
quired by Federal regulations on many nar-
couc-contammg prescriptions This presenp-
tion calls for a Qass A narcotic, codeine
sulfate, m a quantity not more than one grain
per dose, which, when combined with a ther-
apeutic dose of aspirin, is converted mto a
component of a Qass B narcotic so that the
ofTiaal signature of the presenber is not re-
quired. Any narcotic prescription falling
withm the dcfimtioa of a Class B product
may be accepted orally, in person or by tele-
phone, by the pharmacist from a physician
Also necessary on a narcotic prescnpiion,
such as this, arc the narcotic rcgistciy num
ber of the presenber and his olficc address
While there is a decided tendency on the
part of the medical practitioner to write
simple, 1 ingredient prcscnptions, there arc
still some compound prescriptions such as
the one illustrated m Figure 2 A tj’pical com-
pound prescription may be considered to have
4 distinct portions, known as the basis, the
adjuvant, the corrective and the vehicle The
basis IS the chief active mgredient In Figure
2, chloral hydrate is the basis, and from it
the patient will dtnvc a greater therapeutic
effect than from any other ingredient Chloral
h)dratc is a drug with hypnotic action The
adjuvant is that medicine included to aid or
assist the basis Sodium bromide is the adju-
vant here. It has a sedative action due to the
bromide ion The corrective is that substance
or those substances added to qualify the ac-
tion of the basis and the adjuvant Correc-
tives are used to make other drugs less irn-
laiing or to serve as flavonng agents The
syrup of raspberry is added as a flavor
I^aJly, a vehicle (water m this prescription)
1 $ added to dilute the active constituents to
a reasonable dose size
In a prescnpiion requiring compounding
by the pharmacist, the quantities of the in-
gredients and the total amount of the medica-
uon may be expressed in either apothecaries’
or metric units Occasionally, in certain t}pes
of formulas, the concentration of the active
constituent is stated m percentage
Figures 1 and 2 illustrate prescriptions in
which quantities are expressed m the apothc-
cones’ sjstem These units arc still used la
some prcscnptions, but the proportion of
metric prcscnptions is m die majority and
IS growing, due to the adoption of the metric
system m medical schools Any table of units,
whether It mvohcs weights and measures or
some other problem such as a monetary sys-
tem, IS more convemcot to use if it is based
on the decimal system Tlic use of the mclnc
system m preference to the apothecaries’ sys-
tem IS, m most instances, more convenient to
the physician and the pharmacist
The metne system is used for formulas and
doses of products m the t/-S P , the h/ F , the
NNJ) and the Amcncan Hospital Formu-
lary Service The sizes of many products and
the doses of practically all of the individual
uiuts of the newer products marketed by
drug manufacturers arc given m the metne
syatem Sizes and doses of some new products
Fio 2 Typical compound prescription
and many of the older products are gives in
both the metne and the apothecaries’ sys-
tems
The following prescriptions indicate 2
methods by which metric quantities may be
expressed
5
Mercury bichloride
025
Resorcinol
4
Pormic acid spirit
30
Lavender oil
075
Alcohol
150
Water to make
240
In the prescription munediately precedmg,
the decimal points are placed properly one
under the other, and it is understood that
the dry, weighable substances (mercury bi-
chlonde and resorcinol) are called for in
grams, whereas the quantities following the
liquids refer to miUiiiters This prescription
directs a total volume of 240 ml of solution,
a quantity which readily can be placed m an
8-fluidounce bottle Volumes of 100 mL, 200
ml and other amounts which do not approxi-
mate apothecary volumes for wbiw con-
containers are available are not dispensed so
conveniently Prescription bottles manu-
factured to contain metric amounts are not
available at present, although it is probable
that, as the need becomes more apparent,
they will be supplied If a iOO-ml presenp-
tsow vs dispensed vn n 4 oz, botde, the wn-
tamer will be considerably less than full and
the partially filled bottle must be explained
to the average patient. The explanation can
be accomplished by means of an “excuse
label” which merely bears the statement that
the prescnption has been compounded ac-
cording to the physician’s directions, and,
owing to the nature of the prescnption, the
bottle is not filled completely
A still simpler form of excuse label states
’Due to nature of contents, this bottle is
not filled completely ” There are some com-
binations of mcdicmals which are unsafe
when dispensed in well filled containers, but
which can be dispensed safely m oversize
6 The Prescnpiion
comamcrs One example u a cough mixture
composed m part of squill s)rup and am-
moniurn carbonate The effervescence is slow
and may not be completed at the umc the
prescription Ica\cs tbc pharmacy Therefore,
It is desirable to dispense a 4^z. quantity
of this combination m a 6<oz. bottle vvhich
contains the 2*oz. space in uhich the evoUed
gas can be compressed without danger of
bursting the bottle
n
Codeine phosphate | 48
Ammonium chlonde 8 [
Wild cherry sjrup to make 120 I
In the prescription immediately preceding,
the vertical line serves as a decimal point
Every portion of the number to the left of
the Ime indicates the whole number of grains
or milliliters, while the figures to the n^t of
the line indicate tcnilis, hundredths, etc., of
a gram or miihhtcr The amount of codeine
phosphate usually would be read as 480 mg ,
although it might be expressed as 48 eg or
04SCm
For convenience, the vertical line may be
prmted on the prescription blank If it is not
already on the blank, some physicians make
a practice of drawing m the vertical line to
clunioatc misintciprciatton of quantities, os
illustrated in Figure 3 If die figures colling
for a senes of ingredients are made m such
3 manner iliat the decimal pomts do not fall
one beneath the otiicr, the pharmacist may
have difficulty m interpreting the presenp-
tion
Figure 4 illustrates a prescription in which
the quantities are not WTitten m a straight
vertical line Tlic quantity of phenol (4 Gm )
easily could be read as 0 4 Cm Not only is
the 4 set over to the nght toward the teaths
position, but the dot over the / in calcls u so
located that it might be mistaken for a
decimal point. The usual quantity ol phenol
Dosage Caiculohons 7
m such a dermatologic preparation is be-
tween 1 and 2 per cent However, since
sumJar prescriptions wnttea by tins physician
had been filled at this particular phanna<^, it
was an easy matter tor the pharmacist to
interpret the prescnptioa
If there ever is any doubt on the part of
the pharmacist as to the latentions of the
physician, be should telephone the physician
to have him clarify the questions
Figure 3 illustrates a prescription that
necessitates calculation of the amounts of the
active ingredients Percentage strength m
ointments is of the weight-m weight t^
Sixty Gm is to be the total weight of the
omtmenL Five per cent of 60 Gtn or 3 Gm
IS the quantity of salicylic acid to use There
will be twice this amount (10 per cent of 60
or 6 Gm ) of benzoic acid required
Calculations w/w in the apothecancs’ sys-
tem utilize the figure 480 (grains per ounce)
If one were to make 1 oz. of a 10 per cent
omtment of ammomated mercury m white
omtment, he would use 10 per cent of 480
or 48 gr of the active constituent and enough
white omtment (432 gr ) to make the
finished product up to a total of 480 gr
The prescription m Figure 5 offers a
problem m the selection of a vehicle for the
penicillm solution The pharmacist finds it
necessary, therefore, to have a good knowl-
edge of the various buffered, isotonic solu-
Fig 5 Buffered solution prescription
tions and the adjustment of pH of these
vanous solutions In the transcription of this
prescnption is the abbreviation o u (oculo
utro), meaning "each eye ”
As a general rule, Roman numerals are
used with apothecaries’ umts and Arabic
figures are used to designate quantities m the
metnc system The prescnption m Figure 6
IS unusual m that Roman numerals are used
with the metric volumetric unit, cc In writ-
ing the duecuons to the patient, the physician
used an Arabic figure for 2 drops rather than
the Roman numeral generally employed with
such abbreviations
DOSAGE CALCULATIONS
The quantities of drugs m a prescnption
often are wnlten for a single dose with m-
structions to send a specific number of doses
In the following prescnption, a 5 gr quantity
of potassium iodide is directed to be dis-
GS. yf-
FxO 6 Unusual modem prescnption
8 Ths Prescnption
Table 1 Apf’Roxl^^ATE Equivalents in
Fluid Measure
HousmioLo
Measure
Apothecaries Metric
Teaspoonful
fl 5 1
Ami
Dessertspoonful
fl 3 a
8 ml
Tablcspoooful
fl 3iv
15 mL
Wineglassful
fl
60 ml
Tcacupful
fl ^iv
120 ml
Tumblerful
fl ^Vlll
240 ml
Cupful
fl ^ VUl
236 6 ml •
* Ajnmcan StanJanh AuccialiM New York
17 N Y
solved in enough cherry syrup to make 1
iluidram Twenty four such doses or 24
(luidmms (3 fluidounccs) is the (quantity to
be dispensed The dose ( 1 fiuidrom) is trans-
lated to the patient as I tcaspoooful The
required 120 gr or 2 drams of potassium
iodide should be dissolved m enough of the
s>rup to male 3 fluidounccs
n
Potassii lodidi gr v
S}rup Cerasi q$ flSi
M Ft soluuo D t d xuv
Sig flStmaquatid pc
The size of the household teaspoon varies
considerably, and a given teaspoon wiU yield
diflcrcot volumes of mcdicmc dependent on
the technic of the person mcosuriog the
powder or the liquid * In a sundar manner,
the dessertspoon, the tablespoon and the
teacup vary in size, depending on the meas-
uring devices avadablc m diflcrent house-
holds USP X recognized (he volumes of
the teaspoon, the dessertspoon and the table-
spoon to be ‘ 4 cc 8 cc and 15 cc or 1
fluidrom, 2 fluidrams and 4 fluidroms, re-
spectively Some ph)siciaas conunuc to wntc
prescriptions in the apothecaries’ s)stcm (see
preceding prescription), m such eases,
wherever fluidram is cmpIo)cd it is assumed
to mean teaspoonful hfcdicmc graduates ore
available, those cunemly seen in pharmacies
ore standardized m terms of 8 icospoonfuls
to the fluidouncc Accordingly, the household
measures would have the values indicated in
columns 2 and 3 of Table 1
In view of tlie fact that the American
Standards Association has established on
Amencon Standard Teaspoon as contammg
4 93 ci: 0 24 ml , and recognizing that the
majonty of people will use teaspoons ordi-
narily available m the household for the ad-
ministration of medicine, the U S P Revision
Committee specified m USP XV that the
teaspoon may be regarded as being equiva-
lent to 5 ml Onginally, the Committee added
that the dessertspoon and the tablespoon may
be Kgarded as representmg 10 and IS ml ,
respectively, but this last statement was not
included m the USP text USP XVI
specifies that the teaspoon is equivalent to
5 ml
'The Amencaa Standards Association
recognized 14 fl 5 as the apoihccancs’ equiv-
alent of the teaspoon The Aracncan Stand-
ards tablespoon ts 14 79 it 0 73 ml (VS 11
and the cupful is 236 6 ± H S ml (8
fl 3)
It should be pointed out that tables of
household measurement in cookbooks also
recognize 3 tcaspoonfuls as bemg equal to
1 tablcspoooful
Some manufacturers, in labeling oral
liquid preparations intended to be admmis-
ter«i in teaspoonful quantities, specify the
quantity of medicinal contained m 1 tea-
spoonful to be 5 ml 'Thus, approximately
only 6 doses are available m I uuidounce of
liquid However, a few manufacturers specify
(he quantity of mcdicmal in a 4 ml tcaspoon-
ful. accordingly, there are approximately 7Vi
such doses m each fluidouncc of liquid Such
labeling IS found for products which have
been on the market for some ) cars
Another unit of volumetric measure which
vanes considerably is the drop This unit is
used to measure doses of potent remedies and
frequently is confused with the mmun The
mmim is alwa)s one sixtieth of a fluidram,
but the drop vanes m size depending on a
number of factors One factor contnbuting
to the vanability of the size of the drop is
the surface from which the liquid is dropped,
iQcludmg the external dianjcier of the de-
livery end of the tube if a tube is used to
produce the drops Other factors affecting the
size of the drop arc surface tension, die den-
sity and the temperature of the liquid and
the rate at which the drops are formed
The USP. defines the official medicmc
dropper as having a delivery end 3 mm. m
Prescription Procedure 9
external diameter and adjusted to deliver 20
drops of water, the total weight of which is
between 0 9 and 1 1 Gm , at a temperature
of 15‘’C
Standard droppers will deliver drops of
relatively uniform size with a given liquid, but
may give drops of a different size with an-
other liquid A dropper which delivers 20
drops per milliliter of water may deliver as
many as 50 drops per milliliter of alcohol
Therefore, it is necessary to consider the
nature of the liquid bemg measured and to
adjust the dose accordingly
The pharmacist may prepare a number of
stock solutions which commonly are used m
such small quantities that it is desirable to
express these quantities m terms of drops
Liquefied phenol, amaranth solution, solu-
tions of other coloring agents and flavoring
oils Of alcoholic solutions thereof serve as
examples If these solutions are stored in
dropper bottles, the dropper of which has
been standardized for the particular liquid
Its bottle contains, the process of compound-
ing can be facilitated
PHARMACEUTICAL LATIN
Latm has been used as the language of the
prescription because it is the language of sci-
entific nomenclature and is used m the sci-
ences in general Smce it is a dead language.
It is less likely to be altered than are the mod-
em languages It is a umversal language,
Latm tenns are definite, whereas the ver-
nacular names of drugs are characteristic of
certam localities Latin was the language
of oUcial nomenclature until publication of
USP XIIl and N F VIII, when English
titles were hsted first and I^tin titles were
placed second US P XVI and N F XI do
not list Latm titles
The majority of prescriptions today pre-
sent a mixture of English and Latm The
names of the ingredients are usually m Eng-
lish or m an abbreviated form which may
represent either Enghsh or Latm titles, while
the directions to the pharmacist and to the
patient commonly are in abbreviated Latm
Only very rarely is a prescription written en-
tirely m Latm There are many prescriptions
calling for the specialty products of drug
manufacturers which are designated by titles
mcapable of ready Latmization
So long as any Latm words or abbrevia-
tions appear m prescnptions, the pharmacist
must be able to mterpret them correctly This
problem is not usually a difiicult matter as
the terms most commonly used are recog-
nizable at a glance after sufficient expenence
has been gamed
The abihty to explam why the vanous
terms possess their particular grammatical
coostnictjon is quite another story One must
have a knowledge of the vanous declensions
of nouns and adjectives, the conjugation of
verbs, the uses of prepositions and, occa-
sionally, the interpretation of idiomatic ex-
pressions Latm is a highly mfiected language
The changes m the words, or inflections, are
used in Latm to show case and number of
nouns, case, number and gender of adjec-
tives, and voice, tense, mood, person and
number of verbs
There arc 6 cases for Latin nouns and ad-
jectives, but only 2 of these are used exten-
sively m pharmacy — nommative and geni-
tive The stem of the word is that portion
which does not change lo any of the various
mflected forms To the stem is added the
necessaiy ending to form each case One ex-
ample will suffice at this pomt The Latin
for tincture is tmctura (nommative case)
and the Latm for belladonna is belladonna
(nommative case) The stems of the words
are tinctur and belladonn, respectively The
prescription form for tmcture of bell^onna
is uncturae beWadonnae (both words m the
gemtive case for limitation)
For 3 complete discussion of the subject,
the student is referred to one of the textb^ks
devoted entirely to pharmaceutical Latm*
In Table 2 are listed pharmaceutically use-
ful Latm \w3rds and phrases with them ab-
breviations and meanmgs
PRESCRIPTION PROCEDURE
Receiving the Prescription
hi the majority of pbannacies, it is the
practice to have a registered pharmacist per-
sonally receive the prescnption from the pa-
tient or the person who presents the pre-
senpuon for the patient The pharmacist can
serve in this capacity m a more dignified and
noi Table 2. Lati»j Words AND Phrases
Term or Phrase
Abbrevutiov
Meamno
aadum
acid, Ac.
an acid
ad
ad
to, up to
addaturcum tntu
add. cumtnL
adde, addatur
odd.
add, let be added
ad libiium
adlib
at pleasure, as much as one pleases
admove, admovcatur
admov.
apply, Jet be applied
ad partes do(cDtes
ad part, ddent.
to the painful parts
agiu, agitetur
agil.
shaLc, sltr, let it be shaken or stirred
albus, >3, 'Um
alb.
ampulla
ampuL
an ampul
nfia
aa. aa
of each
aate
0.
before
ante cibos
ac.
before meals
ante cibum
ac
before food
anutoxmum
aoutox.
an onlitoua
aqua
water
aqua bullieos
aq bulL
boiling water
aqua dcstdlata
aq dest
distilled water
aqua fcr>ciu
aq ferv.
hot water
aqua foatis
aq font
spnng water
aqua pura
aq pur.
pure water
aromaticus, ^a, -um
arom.
aromatic
balneum
bain.
balneum vapom
balo. >3p.
a steam bath
balsamum
bols
balsam
bene
bene
well
bum die
bid
twice a day
bis terve m die
bud.
2 or 3 times a day
bronudum
brom.
a bromds
calcium
calc , Ca
calcium
capiat
cap
let him take
capsula, cspsulae
cap , caps
a capsule, capsules
carbooas
carb.
carbonate
catapla&ma
calapl.
a cataplasm, poultice
centum
C.
100
centum
ccraL
cerate
charta
chart
paper, powder
charta ccrata
chart cent.
waxed paper
chartac
chart
papen, powdea
chanuJa
chart.
(small) paper, powder
chlondum
chlond.
chloride
cochleare ampluni
coeb. ampi
tabicspoonful
cochleare magnum
COCh.RUg
tablespoonful
cochleare medium
coch. mc^
dessertspoonful
cochleare parvum
coeb. parv.
teaspoonful
collodium
collod.
collodion
collunanum
collun
nasal douche
coIl)num
coU)T.
on eye lotion, an c)ewash
compositus, -a, -um
comp .CO.
compound
congius
cong ,c.
a gallon
consperge, coospergantur
comperg
sprinkle, let be sprinkled
contmus, -a, -um
contus.
brutseJ
cum
c,c
with
cum aqua
cumsq.
With water
da. delur, dentur
d., dec
give, let be given
decoctum
decoc.
a decoction
Table 2 Latin Words and Phrases {Continued) 1 1 1 J
Term or Phrase
Abbreviation
Meaning
decubitus
decub
having gone to bed
degluUalur
deglut
let be swallowed
dcnufricium
dentifnc
a dentifrice
demur tales doses
d t d
give of such doses
diebus al terms
dieb alt
on alternate days
dilutus, a, um
dll
dilute (adj ), diluted
dunidius, a, um
dim
one half
directiones
dir
directions
dispcnsa, dispeosctur
disp
dispense, let be dispensed
dividatur la partes aequales
div mpar aeq
let be divided into equal parts
divide, dividatur
div
divide, let be divided
doses
dos
doses
dosis
dos
a dose
durante dolore
dur dot
while pam lasts
elixir
elix.
an eliXir
emplastrum
emp
a plaster
emulsum
emuls
emulsion
ess^Ua
ess
an essence, spint
et
et
and
ex aqua
ex aq
m water
ex modo praescripto
emp
ID the manner prescribed
extractum
ext
an extract
fac
ft
make
fexTum
ferr
iron
Sant
ft
let them be made
fiat
ft
let It be made
fiat lege axtis
fla
let be made according to the law ol
the ait
filtra
filt
filter
fluidextractum
fidext
afluidextract
folium
fol
leaf
gargansma
garg
a gargle
gelstum
geL
agehieUy
^yceritum
^ycer
aglycente
glycerogelatinutn
glycerogel
glyccrogelatin
granum, grana
gf
a gram, grains
gutta, guUae
drop, drops
guttatun
guttat
drop by drop
bora decubitus
hor decub
at bed hour, at bedtime
bora somni
h s
at bedtime
hydrargyrum
hydrarg
mercury
in
lU
m, into, within
maqua
m aq
m water
in aqua buUiente
in aq bull
m botliog water
m die
ID d.
JO a day
infusum
inf
an infusion
inhalatio
inhal
inhalation
lounctum
lounct
inunction
IQ Vitro
invit
in glass
lodidum
lodid
an iodide
kalium
K
potassium
iavalio
la vat
a wash
lege artis
1 a.
by the law of the art
Icviter
lev
lightly
hnimcntum
Im.
a Iimment
liquor
hq
a liquor, solution
Table 2 Latin Words A^D Phrases (.Continued)
Term or Phrase
AEDREtnATlON
hlEANlNa
lotio
lot
a lotion
magma
mag.
amagma, niUlc
magnus, a, Hjm
mag.
large
nuBepnmo
man pnm.
first thing m the mormng
mossa
mass.
mass
mnhiu, a, um
med
medium
mel
mel
honey
misce
ht
you mix
nusce cxactusime
M eucL
mix most exactly
mutura
misL
a mixture
nuttc, mittatur, mittontur
mitt
you send, let it or them be scot
nutte tolls, mute tales
milt loj
send such
modicus
mod
moderate sued
modo dictu
M diet
as directed
modo praescnpto
mod pracs,mp
m the manner presenbed
molUs
moll
soft
moredicto
mor diet
m the manner direded
mucilago
mucii
a mucilage
notnum
Na
sodium
nebula
nebu)
a spray
nthi! album
mhd alb
zinc oxide
nocte
nod
at night
node maneque
noct nuncq
night and monung
non repctatur
non rep
do not repeat
numero
no
number
octonus
O.od
a pint
oculo dextro
ocul dext
in the ngbt eye
oculo sumtfo
ocul simst
m the left eye
oculo utro
ou.ocul uiro.O)
cache) 6
odontalgicum
odont
toothache drops
oleaitun
oleat
on oleoie
oleorcsma
olcorcs.
an olcoresui
oleosaccharum
olcosaccb
Oil sugar
oleum
ol
an oil
omoi hora
omn. hor
cscry hour
omnl mane vcl node
omn m«n >cl nod
every mormog or night
omnt quaiu hora
omn. 4 hr
every 4 hours
omnit
omn
i^i,cycfy
omol sccunda hora
omn 2 hr
every second hour
omnr tcrtia bora
omn lert hor
every 3 hours, every third hour
optimus, a, -um
opi
the best
partes aequalea
pe.
equal ports
porlibusvictbus
part vicibus
m div ided parts (doses)
parvus, a, •um
parv
small
pasta
past
a paste
pasuUus
pastil
lozenge, pastille
per diem
pcrdicm
per day
per os
per os
by mouth
pctroxolinum
pclrox
a petroxolin
phosphas
phos
a phosphate
pilula, pJulae
pj
a pill, pills
placebo
placebo
I please
plumbum
plumb
lead
ponderosui
pond.
heavy
pone
pone
put, pface
post ctbum, post cibos
pc
after food, after meals
Table 2 Latin Words and Phrases (Continued) 113]
Term or Phrase
Abbreviation
Meaning
praecipitatus
ppL
precipitated
pro dose
pros dos
for a dose
pro ratione aetatis
pro raL aetatis
according to age
pro recto
pro rect
rectally
pro re nata
pin
as occasion anses
pro urethra
proureth
urethral
pro usu externo
pro us ext
for external use
pro vagina
pro va^n
vaginal
pulvjs, pulveres
pulv
a powder, powders
pulvis grossus
pulv gros
coarse powder
puivts tenuis
pulv tenu.
fine powder
purus
pur
pure
quantum libet
as much as you wish
quantum placet
q plac
as much as you please
quantum sufScit
qs
as much as suffices
quantum vis
q VIS
as much as you wish
quantum voluens
q vol
as much as you wish
quaque hora
qq hor
every hour
quater m die
4 Ld , qj d.
4 tunes a day
radix
rad
a root
recens
rcc
fresh
recipe
take thou
reductus in pulverem
red mpulv
reduced to powder
resina
res
aresm
ruber, rubra, rubrum
rub
red
sal
sal
salt
saturatus, a, um
sat
saturated
secundum artem
s a
according to art
secundum legem
si
according to law
semel
semel
once
semen
sem
seed
semi, semis
ss,^
one half
semibora
senubor
half hour
sesqui
sesq
one and one half
signa, signetur
S‘g
write, let be wntten
simplex
simpl
simple
simul
simuI
at toe same time
Sloe
s
without
sine aqua
sine aq
without water
SI opus sit
Slop sit,sos
if there is need
sodium
sod , Na
sodium
solutio
sol
a solution
solutio saturata
sol sat
a saturated solution
solve
solv
dissolve
species
spec
a species, tea
spmtus
sp
a spmt
spiritus vini rectiiicatus
sp vin reel , s V r
alcohol
spmtus vini tenuis
sp V 10 ten , s vt>
proof spmt, diluted alcohol
statim
staL
immediately
sulfas
sulf
a sulfate
sumat talem
sum tal
take one such
same, sumcndus
sum.
take, to be taken
suppositona
suppos
suppositones
suppositona rectalia
suppos rect
rectal suppositones
supposvtonum
suppos.
a suppository
syrupus
syr
a syrup
14 The Prescription
Table 2. Latin Words and Phrases {Continued)
Term or Phrase
ABBREVUTtOS
Meaning
tabella, tabellae
tab
tablet, tablets
tabletta
tab
tablet
tales doses
tal dos
such doses
tails, tales, talia
tal
such
ter
t
3 times, tbnee
tere stmul
ter simul
rub together
ter m die
Ltd
3 times a day
tcrquatervcmdie
tqid
3 or 4 tunes a day
linctura
tr.tincL
a tiDcture
tOAitabella
toxitabd
a poison tablet
tnturatio
tnL
a trituration
irochiscus, trochisct
trocb.
a troche, troches
uncia
oz.,$
ounce
unguentum
UDgL
an ointment
unguentiun moUe
uagt moU
soft ointment
ut dictum
ut diet
as told, as directed
utendum more solitio
utend mor sol
use in the usual manner
vaccmum
vac
a vaccine
vel
vel
or
vuium
vin
a wine
vindis. •«
vir
green
volatilis, >0
vol
volatile
zingiber
zz
ginger
unus, a, * 011 ]
i.I
1
duo, duae, duo
u. 11
2
tree, tna
III. Ut
3
quattuor
jv,IV
4
quinque
v.V
5
sex
VI. VI
6
septem
vii.vn
7
octo
VIII, VIII
8
novcm
IX, IX
9
dcccm
x,X
10
undecim
xi.XI
It
duodeciffl
XU. XII
12
trcdccim
UU.X111
13
qualtuordecim
XIV, XIV
14
qmndeetm
XV. XV
15
sedccim
XVI, XVI
16
septcndecim
XVII, XVII
17
duodcvigmti
xvui. XVIII
IS
undcvigmti
XIX. XIX
19
viginti
XX, XX
20
vigmli unus
XXI, XXI
21
VlgLDtlduO
XXII, XXII
22
tngecta
XXX, XXX
30
quadraginta
xl, XL
40
quinquaginta
I,L
50
scxagmta
Ix.LX
60
scptuagmta
]xx.LXX
70
octogmta
Ixxx,LXXX
80
oooagmia
xc.XC
90
centum
C
100
Prescription Procedure 15
a more efficient manner than can some other
employee of ihe phannacy There may be
questions asked by the patient which need
ffie attention of the pharmacist
If the patient’s name and address do not
appear on the prescription, the receiver should
obtain this mfoimation If the prescnpUon
IS mtended for a child, the age of the patient
for whom the medicine is intended should be
recorded on the prescnpUon Somcphysicmns
supply this mfotmation on the order
The receiver of the prescnption should
ascertam whether the pauent (or his agent)
wishes to wait for the medicine, return for it
at some specified ume or have it delivered
On this information will depend the order m
which the prescriptions then m the pharmacy
will receive the attetiuon of those compound-
mg Well-designed pharmacies have waiting
areas provided for those who wait for their
prKcnpUons
Processing the Prescription
Some of the larger pharmacies use a claim-
check system to prevent mistakes m handimg
prescnptions A pilot sheet such as that illus-
trated m Figure 7 may be used Hus sheet
has a space for the pauent's name and ad-
dress and spaces where the receiver can place
his idenuty and note whether the pauent will
wait for his prescnpUon or return for it later
The pilot sheet is divided mto 2 parts, de-
signed so that the smaller part can be tom oil
and can be used as a claim check The ma]or
poition of the sheet cames the same number
as the claim check and follows the written
order through the pharmacy while the medi-
cine IS prepared This claim-check number,
of course, bears no relaUonship to the senal
number that will be assigned to the presenp-
Uon and the finished product. Most pharma-
cists using the pilot-sheet system stamp the
current date on both the claim-check portion
and the remamder of the pilot sheet Some-
Umes this date is of value m keepmg records
The pilot sheet and the prescnpUon are
taken by some compounder who puts his
uuuals m the space provided for his idenUty
and then proceeds to fill the prescnpUon
When the prescnption i$ labeled, Ihe senal
number of the prescnpUon is stamped on the
pilot sheet as well as on the label and the
pharmacist sets down m the space provided
the price to be charged for the product The
pilot sheet is attached to the finished product
and these arc laid aside to be claimed. Space
16 The Prescnption
IS provided on the sheet for the lisuag of ad-
ditional purchases If the bill is paid, the
cash register stamps the amount paid on the
pilot sheet If the bill is to be charged, the
pilot sheet is so marked and is sent to the
bookkeeper, who makes the proper charges
Many prescriptions are received from the
physician by telephone In fact, many phar-
macies have duect-Ime telephones with phy-
sicians who need only to lift the receiver of
their ofSce telephone to speak personally
with one of the pharmacists in that particu-
lar pharmacy The telephone saves much of
the physician’s time either while he is visiUng
bis patients m their homes or while be is m
his olBce, because he does not have to wnte
out the prescriptions
Usually, the pharmacist taking the dic-
tated prescription over the telephone will first
write It out m abbreviated form on scratch
paper and m a few moments wnte out the
good copy which is to be kept on file The
pharmacist must use care m ukmg presenp-
tioos by telephone that he gets them correctly
If any question anses about the phystetao’s
wishes, the pharmacist should hold the con-
versation o^n until he is sure he has the
prescription correctly in mind and enough
of It on paper to transfer that mformation m
Its enure mtent to the good copy
One real advantage of the telephone to
both the pharmacist and the physician is that
It develops a good interprofessional relauoo-
ship Wtule the pharmacist bos the physician
on the telephone, he can quesuon any possi-
ble mcompaiibiliues Many times, the phy-
sician mquircs about new drugs or new fonns
of adnunistration The pharmacist can be of
real service as a consultant to the physician
if he studies the new products and is ^ert m
ansHenng the physician’s questions
DISPENSING THE PRESCRIPTION
Dispensing mcludcs reading the presenp-
Uon, checking the presenphon for safety,
compounding and/or mcasunng the mcdica-
uon, packaging the mcdicauon, labelmg the
presenpuon, checkmg the presenpuon, rc-
cordmg infonnauon on the prescription and
filing the presenpuon
Dispensing pharmacy is the final step in
the presentaUon of medicaments m a form
suitable for administrauon to the pauent Al-
though dispensmg pharmacy is based on
sound scientific principles, it is desenbed os
an art, and much of the personality of the
pharmacist is evidenced by the prescnptions
which he compounds
Neatness, accuracy and speed are 3 quali-
Ues that must be developed by the mdi-
vidual who wishes to become a dispensmg
pharmacist Neatness and accuracy must be
developed first, speed comes with expe-
rience
Nothing can impede the progress of a
pharmacist as much as a disarranged counter
on which to compound his presenpuons A
slovenly dispenser wdl never become a good
one The habit of leaving bottles and utensils
in disorder on the counter, or of allowmg
dirty apparatus and contamers to collect on
or in the prescription case, mdicates an un-
disaplmed atutude which will not express
itselx m accuracy
In many smt^er pharmacies, only a small
part of the pharmacist’s ume is spent in the
compounding of presenpuons Whatever the
rauo of professionalism to merchandising, a
portion of the pharmacy should be set apart
wherein the compounding of presenpuons
can be conducted without intemipuon
Dunng the time a pharmacist is com-
pounding any one prcscripUon, that pre-
senpuon should be given his undivided at-
tention NVhen his attention is not devoted
cnUrely to the presenpuon, errors arc likely
to creep m For this reason, it iS a good
polity to keep the presenpuon room clear of
everyone except the pharmacist If visitors
do happen to come m, the pharmacist should
complete his visiting and then return to his
work
Reading the Prescription
The legibihty of a presenpUon depends
on the experience of a pharmacist as well as
the penmanship of the medical pracuuoner
A pharmacist who is accustomed to handling
pniscnptions wntten by certam physicians
will cxpcncncc no diQicuIty in reading them,
whereas another pharmacist may have trouble
with portions of the orders As the pharma-
cist becomes more experienced m rccogniz-
Dispensing fhe Prescription 17
mg certam drug combinations and diarac-
teristic directions for the compounding and
the uses of those combmations, he finds it
easier to read prescnptions
A pharmacist with experience m readmg
the penmanship of the physician who wrote
the prescription m Figure 8 probably would
have little difficulty in mterpreting his inten-
tions The inexperienced pharmacist, how
ever, might have considerable trouble in
reading it, and might even find it necessary
to consult the physician The prescnption
calls for a half ounce of horse serum oint-
ment and an equal quantity of Bates* oint-
ment with 2*/4 per cent silver nitrate, to be
mixed and dispensed m a collapsible tube
with a rectal tip applicator The patient is
directed to mseit the ointment at bedtime
daily for 7 days
Fig 8 Prescription presenting a problem
in legibility
Age (in months)
ISO
X Adult dose = Infant’s dose
Dr Clark’s Rule assumes the average
weight of an adult to be 150 pounds There-
fore,
Checking the Prescription for Safety
Before a pharmacist attempts to com-
pound a prescnption, he must understand
all of It thoroughly He must be satisfied that
there are no dangerous overdoses or mcom-
patibilities If any portion of the prescnption
IS not understood, or if be has detected an
mcompatibility, he should consult the phy-
sician who wrote the order Many pharma
cists hesitate to call the medical practitioner
about these matters, but, if the calls are
executed tactfully, there is no reason why
they should not create a better understand
mg between the men of both professions
The dose of each drug m a prescnption
should be checked carefully by the pharma-
cist before he proceeds to fill the prescnp-
tion It should be emphasized that, m the
event of injunes or fatalities from prescnp-
tions containmg overdoses of dnigs, the
pharmacist can be held criminally liable
Those factors which the pharmacist should
take mto account m judging the danger or
the safety of a dose of medicme follow
Age or Weight of the Patient Tliere are
a number of methods for calculating the
fractional part of the average adult dose
which an i^ant or a child can take safely
One method (Dr Frieds Rule) is based on
the assumption that an adult dose of a drug
can be tolerated safely by a child when be
reaches the age of ISO months Therefore,
Weight of
child in pounds . ^
jjg X Adult dose w Child s dose
As a general rule, a naturally heavy individ-
ual can withstand larger doses of medicines
than a person of less weight
Dr Youngs Rule is very popular
Ag^+ 12 ^ — ChJds dose
Dr Cowling’s Rule is based on age m
years at next birthday (present age +1)
■ — X Adult dose = Child s dose
24
Route of Administration. Companson of
the oral doses of drugs with the mtravenous,
the intramuscular, the subcutaneous or the
rectal doses of the same drugs shows that
no valid rule can be estabhshed for predict-
mg the parenteral or the rectal dose of a
drug from the oral dose Drugs which are
absorbed completely from the gastromtesti-
nal tract will probably have equal parenteral
and oral doses, whereas drugs which are
poorly absorbed by the oral route will have
smaller doses parenterally than orally The
pharmacist must know the range of s^e and
cffwuve doses for the prescribed drug when
admmistered by the presenbed route Since
many drugs cannot be admmistered safely
18
The Pfescriphon
by all parenteral routes, the pharmacist
should also make certam that the prescribed
route of admimstratiOQ is safe for the par-
ticular drug
Fharmaccuticfll Dosage Form. The vehicle
of a prcscnption or die degree of subdivision
of a solid drug m the particular dosage form
affects the safety and the therapeutic elEcacy
of the prescription K polyethylene gl>col
IS used as the base for an ointment contain-
ing benzoic acid and salicylic acid, the con-
centrations of the acids should be only half
what they would be if a hydrocarbon oint
ment base were employed, because the acids
are more active m the polyethylene glycol
base than they arc m the hydrocarbon base
The degree of subdivision of an active drug
also may affect its therapeutic activity and
potential toxicity Agam using an omtmcnt
as an example, if polysorbate 80 is mixed
ivith coal tar prior to incorporation of coal
tar mto the ointment base, a lower concen-
tration of coal tar must be presenbed This
IS due to the fact that the subdivision of coal
tar brought about by prior mixture with the
polysorbate 80 results m a more pronounced
action on the sbn This subject will be more
thoroughly discussed in Chapter 2
Frequency of Admmistration. If the drug
has a fleeting action, there should be little
concent about the short intervals of time be-
tween doses On the other band, many potent
drugs have a cumulative action Toxic mani-
festations may appear, even though the m-
dmdual dose appears to be safe, if the fre-
quency of administration is too great. There
should be more concern about these drugs
when prcscnplions of large quantity are
ordered which make possible a large num-
ber of doses over a short time Among such
cumulative drugs arc bishydroxyooumann,
digitoxm and thyroid
Sometimes, the author of a prescription
has a parucularly good reason for the appar-
ent overdose of a drug and he perhaps in-
tends the dose he has prescribed, but the
pharmacist nevcrtlicless should consult the
practitioner to satisfy himself that the dose
IS correct
There arc many factors mvolvcd conccra-
mg the safely of a given dose which the phy-
sician alone has the opportunity of knowing
A nervous person usually requires a greater
quantity of sedauve than a nonnal person.
whereas a phlegmatic person usually requires
a quantity of stimulant that seems abnor-
mally large The doctor’s patient may have
developed a tolerance for certam drugs and
consequently need abnormally large doses
for the desired effect Gross tolerances may
exist in the patient who may have been tak-
mg one sedative for some time and has de-
veloped a tolerance for other member seda-
tives of the group as well as the one taken
Pathologic conditions sometimes demand
larger doses of certain drugs There may be
an unusually large amount of pam accom-
panying the conation and abnormally large
doses of narcotic may be required These are
some of the charactcnstics pertammg to the
patient which only the physician knows
When he writes the prcscnption, he could
underlme the drug and the quantity to direct
the pharmacist’s attention to the fact that he
IS aware of the unusual dose be has called
for TheleilersQR (quantum rectum, quan-
tify venfied or correct), both apothecancs*
and metric systems or both Arabic flgures
and Roman numerals may be used for the
same purpose
COMPOUNDINO TUB PRESCRIPTION
A number of years ago the majority of
prescriptions required compoundmg, that is,
the pharmacist weighed or measured several
dru^ and combmed them into one com-
patible, easily admmistercd dosage form
Today, relauvciy few prcscnptions mvolve
compounding (as few as I per cent m some
localities), but the pharmacist must still
possess the knowledge and the skill m com-
pounding to the same degree that be for-
merly did, so that he can prepare the pre-
senptions and special formulations that arc
called for In fact, with the development of
new pharmaceutical aids — surface active
agents, suspending agents, preservatives, syn-
thetic flavors — today’s pharmacist has more
opportunity to use his specialized skills than
did his predecessor The exapicnts and the
procedures he uses in compounding may
have a pronounced effect on the thcrspcutio
efficacy of the drug
No one set procedure can be designed for
compoimding ml prescriptions Each class of
prescription and, oftentimes, each presenp-
tion wtihm the class requues its own cbarac-
icnsuc procedure The properties of the m-
Dispensing the Prescription 19
gredients and even their quantities alter the
methods that should be emplo)ed to fill the
prescnption For a complete discussion of
prescriptions represenlmg each of the vari-
ous classes of pharmaceutical preparations»
see the respective chapters m which they are
discussed
Two essential factors m the compoundmg
of prescnptions are quahtative and quanti-
tative accuracy Quahtative accuracy is prob-
ably the more important of the two, but re-
sults of either qualitative or quantitative
maccuracy are obvious The most important
precaution to be observed m the achieve-
ment of qualitative accuracy is to check the
labels of the contamers of stock drugs
After the pharmacist has read and thor-
oughly understands the prescnption, he
should assemble all the mgredients on the
prescription case, placing ^em on the left
side of the balance and in the order m which
they will be used As this procedure is earned
out, he compares the labels of the containers
with the names of the drugs on the prescnp-
tion When he weighs or measures the pre-
senbed quantity of each mgredient, he should
lace the stock bottle on the right side of his
alance, again comparmg the labels of the
contamers with the names of the drugs on the
prescription Then he is ready to mix the in
gredients m the proper order to make the
finished prescription
As soon as the pharmacist is through with
the stock contamers, he should return (hem
to their proper storage places By foUowmg
such a procedure, the pharmacist reads the
label on each stock container 3 tunes and
reads the inscnption of the prescription 3
tunes while he is filling the presenpuon —
once when the bottle is taken from the shelf
and placed on the prescnption case, agam
when the weigjung or the measurement is
made and, finally, when the stock bottle is
returned to its proper place on the shelf
Much has been written on the subject of
presenpuon tolerances PresenpUons have
been analyzed and attempts have been made
to establish legal tolerances Regardless of
what tolerances eventually may be estab-
lished, the pharmacist should make every
effort to compound his presenpUons ac-
curately
The P and the A F have established
mdividual standards for official preparaUons,
and most of them seem to approximate a
penmtted error of rt: 5 per cenL This degree
of accuracy is sufficiently precise for nearly
all thetapeuUc purposes and can be achieved
with equipment ordmanly available m the
pharmacy, in fact, with care, it is possible
to compound with a greater degree of quan-
titaUve accuracy than an error of 5 per cent.
Nevertheless tins value will be selected for
the discussion which follows
It should be understood clearly that noth
mg should ever be said or done to pardon
maccuracy On no account are carelessness
and any tendencies to approximate to be
permitted m any of the acts of dispensmg It
must be emphasized that accurate compound-
mg cannot be achieved by considering it a
procedure to be pracuced only under certam
circumstances It can be achieved only by
developing an exactmg technic and by ngidly
adhenng to such technic regardless of the
pharmacists opinion of the necessi^ for ac-
curacy m any particular prescnption He can-
not decide to compound carefully and exactly
one time and to approxunate on the next
occasion
In mamtainmg a satisfactoiy degree of ac
curaqr in compoundmg, not only must the
medicinal substances be weighed or measured
with care, but also these ingredients must be
handled m a manner to prevent losses of
drugs and diluent m completing the prescnp-
tion Care must be exercised m transfemng
weighed materials and m pounng viscous
flui^ from ^aduates to make certain all of
each mgredient is present m the final mix-
ture Furthermore, if the prescnption calls
for mdividual doses, each dosage form must
contam an accurate fraction of the total
medicmal products present The dosage form
may be either a weighable quantity or a
measured volume Most of the potent medi-
cmal substances are solids Therefore dis-
cussion of weighing will precede that of meas-
urement of volume
A prescnption balance m good condition
is usually sufficiently accurate to weigh faidy
large quantities withm the limits of S per
cent, but its ability to weigh small quantities
within these limits depends on its sensitivity
The sensitivity of a balance may be defin^
as the small^t weight which will disturb the
20 The Prescription
equilibrium of the balance and is determiDed
in the following manner
Carc/uliy adjust the balance to eqmlibnum
and arrest the beam Place the smabestwei^t
on a pan and release the beam If the equi-
librium is undisturbed, anest the beam and
replace the weight with the next larger weight
If this weight does not upset the equihbniim,
repeat the process until the mmimum weigjit
which Will do so IS found. This piirumum
weight designates the sensitivity of the bal-
ance and may be as little as 1 or 2 mg (high
scnsiuvity) Wear on the beanngs and cor-
rosion of knife edges cause a progressive de-
cline in sensitivity and it is not unusual to
find a balance with a sensitivity as low as
10 mg Torsion balances of 120 Cm capac-
ity have a sensitivity of 2 mg when new and,
with proper care and techmc m use, declme
little m sensitivity because of lack of bearmg
surfaces
The method of designating sensitivity de-
scribed above is not to be confused with
sensibility reaprocal, which is the amount of
weight which must be added to one pan m
order to produce a change of one division on
the index plate m the rest pomt of the
balance
The sensitivity of the balance is imponant
when determining possible errors m weigh-
ing small quantities For example, if 100 mg
IS weighed on a balance having a sensitivity
of 2 mg , the actual weight wdl be between
98 rog and 102 mg., a possible error of
± 2 per cent If the sensitivity of the balance
IS S mg , the actual weight will be between
95 mg and 105 mg , a possible error of ±: 5
per ccDL II the scasjtjvjiy d the balance js
10 mg, the actual weight will be between
90 mg and 1 10 mg , a possible error of 10
per cent If one wished to achieve an accu-
racy of ± 5 per cent, he would have to weigh
a minimum of 20 limes the sensitivity of the
balance Since there arc often other opera-
tions subsequent to the initial weighmg, it is
not good policy to weigh the minimum, but
rather to weigh 30 or even 40 tunes the sen-
sitivity of the balance %Vhcn more than one
operation is mvolvcd in compounding, pos-
sible errors may cancel each other or they
may be additive. In the latter case it is obvi-
ous why more than 20 tunes the sensitm^
of the balance should be weighed
When the desued quantity of medicma]
IS too small to be weired with the selected
accuracy, the pharmacist can follow one of
several procedures Tablets of the medicmal
substance may be used, provided that they
are available ui such strength that a number
of them will contam exactly the quantity
needed for the prescription and, also, pro-
vided that excipients and Ellers m the tab-
lets are not objectionable mgredients m the
prescnption Dispensmg tablets of the me-
dicmal may be available for use m the pre-
scription However, it is quite unlikely that
the quantity of medicmal needed would be
exaedy satisfied by one or a segment of the
dispensmg tablet Furthermore, even if a
segment contained exactly the desired quan-
tity, it would be difficult to procure a seg
ment which would be an accurate fraction of
the tablet
A third possibihty is the use of triturations
of potent medicinals prepared in quanuties
large enou^ to mamtain accuracy of the
pr^uct These inturations varv la strength
(usually from \9o to 10%) dependmg on
the requirements for these ddutioos and are
kept ID stock for compounding prcscnptioas
Which call for small quantities of potent
drugs
i^quot Method of Weiglung and Meas-
uring. A fourth procedure for weighing or
mcasurmg veiy small quantiues of drug is
known as the Ahquot method. An excess of
the drug equal to a multiple of the quantity
needed IS weighed or measured, and is di-
luted to a convement weight or volume Then
the aliquot, or part of the dilution which rep-
resents the desired quantity of drug, is used
m the prcscnptJon This method is illustrated
by the foUowmg example
D
Atropme sulfate gr V*
Dist. water q.s ad 13 1
M ct Ft Sol
Sig Gtt u ex. aq 10* before feeding
The sensitivity of the balance is 3 mg ,
therefore, m order to have an error no greater
than lit: 5 per cent at least 60 mg must be
weighed The pharmacist may weigh 1 gr
of atropme sulfate (four tunes the amount
needed), place the drug in a small graduate
and add enough distilled water to give a
Dispensing the Prescription 21
volume of 4 fluidrams Smce he has weired
four tunes the amount of atropme sulfate
needed, he then uses ^ of ±e solution
(which then contains gr of atropme sul-
fate) m the prescnption To the 1 fluidram
of atropme sulfate concentrated solution he
adds sufficient distilled water to make 1
flmdounce This prescription could be filled
just as well (or probably better) by weigh-
mg SIX times the amount of atropme sulfate
actually needed, placmg it m sufficient dis-
tilled water to give a volume of 6 firndrams
of solution and then usmg 1/6 of the con-
centrated atropme sulfate solution in the pre-
scnption niere are several correct methods
of filling each, prescnption when usmg the
Ahquot method The important rule ts, the
particular muUple of the amount needed
which IS weighed or measured is the same
factor by which the resultmg powder or solu-
tion must be divided m order to obtam the
quantity of diluted drug to use m die pre-
scnption The pharmacist chooses a quan-
tity of diluent which will give him a volume
or weight of diluted drug which can be di-
vided amveniently by the multiple he has
chosen for the pure drug and which will give
an aliquot large enough to be measured ac-
curately The pharmacist must at all tunes
keep m mind limitations of his balance,
graduates, and pipets Other examples and
explanations follow
3
Benzalkomiun chlonde 1 SOOO
m sVenle buS« ^ciuViou q s ad 30 red
MiSig gtl,iOUq4hr
Benzalkonium chlonde concentrate solu-
tion IS 17 per cent m strength A volume of
0 035 ml of the concentrate is needed for
this prescnption This volume cannot be
measured accurately, even with a pipet grad-
uated m 0 01 ml However, a volume 10
iimeit that needed, or 0 35 ml , can be meas-
ured accurately with this pipet A volume of
0 35 mL of the concentrate (ten tunes the
amount needed) is added to enough sterile
buffer solution to give a vxilume of 10 ml
Then l/IO of this volume (1 0 ml , which
contains 0 035 ml of the ben^komum chlo-
nde concentrate) is placed m a 30-01] grad
uate, and sufficient stenle buffer solution is
addi^ (slowly, to prevent foammg) to give
a volume of 30 mL If the pharmacist wished,
he could measure 100 times the volume of
benzalkonium chlonde concentrate needed
(3 5 ml ), add sufficient stenle buffer solu-
Uon to make 100 ml and then use 1/100 of
this solution or 1 ml m the prescnption The
0 035 ml of concentrate could also be meas-
ured by prepanng a 1 500 solution (I ml
of benzalkomum chlonde concentrate and
enough sterile buffer solution to maVe 85
ml ) and then usmg 3 ml of the 1 500 solu-
tion with a sufficient quantity of stenle buffer
solution to make 30 ml of the 1 5000 solu-
tion called for m the prescnptiou
Belladonna exL 0 004
Penlobarbital sodium 0 010
Acetylsahcybc acid 0 ISO
M Ft Cap 1 d Ld. No IV
Stg 1 Capsule 1 hr before each dental
appointment
The pharmacist should prepare enough
powder for 5 capsules to prevent the neces-
sity of recovering minute quantities from the
mortar m order to bnng each capsule to the
exact weight. Using a balance with a sensi-
tivity of 2 mg., at least 40 mg must be
weired to assure accuracy within 5 per
cent. This degree of accuracy could be
achieved by weighing two times the 20 mg
of belladonna extract needed in the prescnp-
tion, but, smce there are several mampula-
tions to be performed m compounding this
pFesenpUon, four times the necessary quan-
tity IS prepared The 80 mg of belladonna
extract is thoroughly mixed with a sufficient
quantity of powdered diluent — lactose, su-
crose or starch — so that one fourth the total
mixture will weigh at least 40 mg (the mmi-
mum quantity which can be weighed on this
balance with an accuracy of :±: 5 per cent)
If a weight of 300 mg. were selected for the
mixture, the weight of the diluent m this case
would be 300 mg — 80 mg == 220 mg
After thorough mixing, an ahquot consistmg
of one fourth of the 300 mg , or 75 mg , is
weighed and placed m a mortar to be xmxed
with the pentobarbital and the acetylsahcyhc
acid. Fifty mg of pentobarbital soffium can
be weighed on this balance with an accuracy
of better than ::i: 5 per cent.
The dosage m each capsule is to be ad-
22 The Prescriphon
justed by weight Smcc an aliquot of ?5 mg
of belladonna extract mixture was weighed
for the Sv e capsules, each capsule should con-
tain 15 mg of the dilution Therefore, the
total weight of medicinal in each capside ts
175 mg
Labeling
The completed prescnption should be
placed m an appropnate sized container and
the label attached The size of label will de-
pend on the style and the size of the con-
tamer selected It often has been suggested
that the label should be typed before the pre-
scription is compounded Typewnters are
now standard equipment m pharmacies and
labels should always be typed Figure 9 illus-
trates a typical label
It IS customary to mclude on the label such
information as the senal number of the pre-
scription, the patient’s name, directions for
use of the medicine, the date and the pre-
senber’s name Ha^ printed label for the
pharmacy bears the name and the address
of the pharmacy Some states requue the
uutials of the compounder to appear on the
label also Labels of prescnptions that con-
tain narcotics have already been discussed
Labels should be placed properly on the
container, should be smoothed out and should
not be smudged The directions for the use
of the medicine should be clear and concise
As a double check on the class of preparation
dispensed, the pharmacist should list that
class of product m the directions to the pa-
tient "Take one capsule three (3) tunes a
day,” mstead of “one 3 tunes a day ” This
form of double check is particularly of value
to the checker for those products marketed
m more than one form — c g , in tablets and
FiO 9 Label for prescription shown in
Figure 1
capsules This procedure also makes for a
more complete and more professional label
The word ‘ take” indicates an mtemal prep-
aration, although some physicians emphasize
the mode of admmistration by directing the
patient to take one capsule ' by mouth” three
tunes a day
In addition to ducctions for use of a
medication, physicians frequently ask the
pharmacist to place the name of the medica-
tion on the label Physicians may do this by
adding to the duccUons, “Label as such ”
Occasionally, they use along with directions
some identifying terms such as “allergy medi-
cine,” “sleep tablets,” or ‘blood pressure
tablets ” These forms of labeling are obvi-
ously convement to the physician m talking
with his patients and convenient to the phar-
macist m dcalmg with the patients regardmg
refilled prescnptions
Special precautions are necessary when
labelmg preparations mtended for external
apphcation
Additional quahfymg labels besides the
one canymg the imormaiion listed above
occasionwy may be necessary Lotions and
mixtufes snould have ' Shake Well” direc-
tions, and prescnptions not mtended for in-
temai use should bear directions ‘ For Ex-
ternal Use Only ”
The patient probably has no means of
judgmg the quality of bis prescnption ex-
cept by the appearance of the product A
good impression will be made on the patient
d his powder papers, for example, are folded
neatly and are placed in a container of good
quality
Properly finishmg the prescnption includes
the wrapping or the placmg of the product
m a prescnption envelope for delivery to the
patient One type of prescnption envelope is
shown m Figure 10
Checking the Prescription
In some large pharmacies prescription
labcb are t}pcd by nonprofcssional help A
pharmacist checks these labels, paces the
prescnption and serves as a checker of the
compounded prescriptions In other phar-
maaes a pharmacist is the labeler as well as
the checker His chcckmg is based on the
appearance of tiie finished product only,
unless be considers it necessary to call m the
Dispensing the Prescription 23
compounder for his explanation of the pro-
cedure employed Whatever the method of
checking, every step which can be taken to
prevent errors is to be regarded as an es-
sential
Information to Be Recorded on the
Prescription
When a prescription is compounded, cer-
tam information should be recorded on it for
easy reference m refilling the prescnpoon
Such mformation includes the serial number
of the prescnption, the date on which it was
compounded, the cost price, the selling price,
the size and the type of contamer used and
special procedures The senal number usu-
ally is stamped on the prescription with an
automatic numbering machme, such as one
of those made by the Bates Manufacturing
Co Such machines can be set to number con
secutively, m duplicate, m tnplicate or in
quadruphcate, or to repeat Duplicate num
bermg allows for numbering the prescnp-
Cion and the label with the same number ff
a pilot sheet system and a daily work sheet
are kept, the numbermg machme should be
set to number m quadrepUcate m order to
put the same number on these records as
appears on the prescnpuoa and the label
l^e date on which the prescnption is filled is
stamped on the prescription with a rubber
stamp Usually, this datmg is done for the
day’s prescnptions when they are assembled
on the prescnption file Often it is necessary
to know when the prescription was filled
ongmally, and the presence of the date on
the prescnption is a convement reference
The cost of the prescnption, mcludmg the
contamer, generally is marked on the pre
scnption in some code which the pharmacist
has worked out The NARD code is
PHARMOCIST, where the first mne letters
are assigned the numbers 1 through 9 and T
IS 0 PMT, therefore, would mean SI 50
Any convement combmation of 9 or 10
different letters will serve as a code If 9
letters are used, zero may be designated by X
In a lO-Ietter code, X is used to designate a
repeat figure — e g , PTX means SI 00 m the
NARD code REPUBLICAN, DEM-
OCRATS, WELD COUNTY, BLACK
HORSE and BLACK HOUSE are a few
examples of codes which might be used.
A code system is used for the cost, because
that 15 the pharmacist’s personal informaDon
The selling pnee is recorded m Arabic figures
because it is announced to the patient and
there would be do point m using a code sys-
tem for It, Selling pnee is necessary on the
prescription so that the same price can be
charged for refills
The size and the type of contamer, espe-
cially if It IS an unusual one, special pro-
cedures emplojed m rmxmg the mgredients,
the size and the color of the capsule used if
the medicme was encapsulated and any other
pertment information that will enable the
pharmacist to make the medication look
exactly like the ongmal product — all are
valuable bits of information in case a refill
IS called for If, on refill, the medication does
not look exactly like the ongmal product the
patient obtamed, be sometimes becomes
apprehensive for fear some error has been
made m compoundmg his medicauon Even
a contamer of a st)le different irom that
24 Tlie Prescripiion
Fio 1 1 Daily work sheet
onginally used, or differently worded direc-
tions, cause some patients to ask questions
about the “different” medicine
In some pharmacies, it is the policy also
to mark on the prescription the identity of the
original compounder and the checker of the
prcscnption The compounder and the
checker of rcMs can be identiffed opposite
the date of reffll stamped on the reverse of
the prcscnption Occasionally, there are
questions regarding procedure which only
the compounder can answer easily
The daily work sheet is a daily record of
the presenpuons filled and usually is de-
signed to mclude such information as that
shown in Figure 11 If a large number of
prescriptions are filled, one record is kept for
onginai prescriptions and one for refills ff
only a few prescnptions are filled in a day, an
extra column can be mtroduced into the
table to indicate whether the prescription is
new or refilled.
The importance of the daily work sheet in
the pharmacy is obvious It shows the phar-
macist at a glance the number of new pre-
scriptions filled, the number of refills and the
total cost and mcome from his presenpuons
each day Occasionally, the dady work sheet
helps to identify a prescnption for a patient
in the event that the label on the container
has been obliterated partially or wholly dur-
mg his use of the medicine
Filing the Prescription
Stnngmg the prescriptions on wires, past-
ing them m books and pasting them on filug
cards arc procedures which are pracucally
obsolete Some pharmacists lie the presenp-
uons m bundles of SOO and place 2 bundles
in a box, thus filing the orders in boxes of
1,000
Another cffccuve method of filing pre-
senpuons IS to bmd them in books of 500
each and keep the books m a steel filing
cabmet of the size intended for 4 by 6 mch
index cards The books are formed by loosely
tymg the presenpuons m a cover of ligbt-
wci^t cardboard and covenng the back of
the book and the stnng with bindmg tape
The range of senal numbers is indicated by
large numbers on the back of the book The
books arc placed m the cabinets numencally
and with the number side (back) up so as to
be easily visible when the drawer is opened
There are on the market a number of
prescnption files of different styles Each
will bold from 500 to 1,000 presenpUons
usually on a pair of wires or on a rod The
files generally are cootamed m a cardboard
or metal box or a cabmet of appropriate size
Some pharmacists use a microMmmg de-
vice to photograph each prescnptioa and
thus file ^e prescnptions on reels of 16-mm
film This system is used conveniently, and
conserves space m prcscrvmg the records It
IS especially valuable for filmg the older pre-
senpuons, which are not used so frequently
as arc those filled more recently
REFILLED PRESCRIPTIONS
Narcotic prescnptions cannot be refilled
under any circumstances In order to obtain
more of the medicme, the pauent must pre-
sent a new presenpuon, or if the narcouc
drag IS m the oral classiCcauon (Class B),
the physician can give the pharmacist a new
prescnption by telephone
Accordmg to the Federal Food, Drug and
Cosmeuc Act of 193S, prescnptions calhng
for such drugs as barbiturates, chloral and
other hypnoucs and the sulfonamides cannot
be refill^ without the consent of the pre-
senber However, the provisions of the Act
were not enforced rigidly until much later,
when the authonty of the Food and Drug
AdnuDislrauon was defined by decisions from
court cases and the Durham Humphrey
Amendment (October 26, 1951 ) to the Act
Any drug bcanng the presenpuon legend,
' Caution Federal Law prohibits dispensmg
without presenpuon” or Caution To be dis-
pensed only by or on the presenpuon of a
physician, dentist or vetennonan,” cannot be
dispensed on the refill of a presenpuon unless
the presenber has authorized such acUon.
The presenber can authorize a reasonable
Refilled Prescriptions 25
number of refiJs on the onginal prescnption
or he can authorize them by written request
or by telephone The act of dispensmg a drug
contrary to the provisions of the amendment
shall be deemed to be an act which results
m the drug bemg misbranded while held for
sale
If a physician does not want a prescnp-
tion to be refilled, he may so indicate by wnt-
mg on the prescnption non rep or non
repetatur — not to be repeated He may direct
that the prescription can be refilled only once
by so marking it
Figure 12 illustrates a prescription blank
prmted to mdude a convement method by
which the prescnber can mdicate the num-
ber of times he wishes the prescnption to be
refilled Simply by encirclmg the appropriate
square or set of letters m the lower left hand
comer, the prescnber can convey his wishes
to the pharmacist The prescnption in Figure
12 may be refilled three times
Some physicians msist that none of their
prcscnptions be refilled without their au-
thorization, desirmg to have the patients re-
turn to their offices for examination to
detenmne whether the same prescnptions
should be continued It may be pointed out
that, according to our defimtion of the word
prescnption, it is an order for a medicme to
be used fay the patient at a particular tune
Therefore, it follows that, as the condition
of the patient changes, his requirements for
a medicme also may change
In labelmg reMed prescriptions, most
pharmacists supply the date on which the
prescnption was Med originally instead of
the date of refill Such procedure keeps the
serial number and the date on the same basis,
and, should the senal number be obhterated,
it IS an easy task to find the patients pre-
scnption m the files However, those phar-
macists who date the label as of the day on
which (he prcscnpaon was refilled can still
trace the patient s original prescnption num-
ber &om the daily work sheet
Fig 12 Typical prescnptioa with refiU authorization system mcludR
26 The Prescription
When a prescnpUoa is re&Ued, it cames
Its same senal cumber regardJess of the cum*
ber of times the order has been repeated. The
advantages of this system are obvious In
order to mcorporate the refills mto the serial
numbenog, some pharmacies follow the
policy of setting the numbering machine
ahead each day by an amount corresponding
to the number of old prescriptions refilled on
the particular day There may be 100 new
prescnptions and 85 refills dispensed on a
ccrtam day If the numbermg machme is ad-
vanced for only the new prescnptions, it will
register 100 more at the close of the day than
it ttgisititd ai the btgmmng ol the day . How-
ever, there were actually 185 prescnptions
(100 new ones and 85 refills) dispensed
Therefore, some phannaues beliese they are
justified m advaccmg the numbenng ma-
chine by the amount (85 in this illustration)
equal to the refills This is accomphshed
simply by setting the numbcnas machine on
’‘consecutive” and stamping a number on
each of the lines used for the refills in the
doily work sheet These numbers arc cot used
to identify any of the prescriptions
The number of times a particular pre-
scription IS refilled and the dates on wmcb
those rcfilb are made is important infonna-
Uon which shoula be recorded on the pte-
scnption This can be accomplished effec-
tively by stamping the refill date on the
reverse side of the prcscnption Opposite the
date should also be mcluded some simple
note to mdicate the autbonzation of the pre-
senber to refill the order, if such authonza-
Uon IS necessary, and the mitials of the
pharmacist who dispensed the refill These
data arc an indication of extent of use of the
medicme by the patient and are valuable for
discussion of the refill problem with thepre-
senber and the paUent Refill mformatioo is
occasionally of value in preventing a person
from bavmg ccrtam of bis prescnptions filled
oftener than proper dosage warrants and in
preventing neighbors and fnends of the pa-
tient from usmg the prcscnption.
While It IS true that some physicians keep
a record on each patient’s chart of requests
for authorization to refill a prcscnption, in
the mnpnty of cases this mformatioo is
cither incomplete or entirely lacking in the
physicians' olBccs This of course refers to
‘ legend ’ drugs Smcc most of the drugs cur-
rently prescribed are ‘legend” drugs, it is
necessary for the pharmacist to obtam au-
thorization from the medical practitioner to
refill the prescription m the majority of m-
stances In those cases where legend dru^
arc not mvolved the pharmacist can exercise
bis own judgment m decidmg to refill the pre-
scnption It should be printed out, howc\er,
that a pharmacist who refills a prcscnption
for the ongmal patient, or for anyone else,
without the autbon^ of the prcscnbing phy-
sician, docs so on his own responsibility As
far as the physician is concerned, the trans-
acuon IS complete v.lstn the phamamst ccsst-
pounds and delivers the ongmal prescription
£ven uoauihonzcd sales of quantities larger
than that caUed for by the prescription are
the responsibility of the pbarmaast
SOME LEGAL ASPECTS OF
PHARMACY
Various state and Federal laws govern the
n^t of certain mdividuaU to dispense drugs
pursuant to medical practiuoncrs’ presenp-
tioDS Registered pharmacists generally are
designated as the persons directly or in-
directly responsible for the handling of the
various drugs The pharmacist should be
thoroughly familiar with the laws of his state
I/suaiiy, pamphlets of state pharmacy laws
are furnished by the state board on request
When the provisions of state and Federal
regulations are not identical, the more strm-
gcotof the two must be observed
Narcotic Prescriptions
According to the Federal Narcotic Law
and Regulanons,* a narcotic is any drug de-
nved from opium or coca or any of its
natural or synthetic derivatives or drugs
which have narcotic properties similar to
those of morphine or of drugs expressly men-
tioned in the Law Narcotic prescriptions
must mclude the name, the address and the
* Relation No 5, U S Treasury Dcparline&t.
Jout Regulations Bureau of Narcouct and In
teraal Revenue Service Starch 5. 1959 Also,
Federal Food Drag and Cosmetic Act and Gen-
eral Reguiauons for lU Enforccmcoi, U S. Depaxl-
meet of Health, Education and Welfare Food and
Drug Adnumstratioa.
Some Legal Aspects of Pharmacy 27
Fio 13 Prescnptioo departmcot of a modem pharmacy
registry number of the piescnber, the date
when wntten, and the name and the address
of the patient Prescriptions for Class A nar^
cotics must be signed by the prescribec On
the label of a narcouc prescnption must ap-
pear the name, the address and the registry
number of the presenber, the name and the
address of the patient, directions for use of
the drug, the date on which the prescnption
was filled and the name, the address and the
registry number of the pharmacy Narcotic
prescriptions must be kept m a separate file
and may not be refilled.
The U S Bureau of Narcotics now cate-
gorizes narcotics m four classes — A, B, X,
and M Class A includes the narcotics which
are considered to be hi^y addicting. Class B
includes the drugs which are thought to
possess relatively little addiction Iiabih^,
Class X narcotics are so-called “exempt” nar-
cotics and Class M narcotics are “esp^ally
exempt.”
Class A narcotics include opium and its de-
nvaUves and compounds pbcnanthienc opium
alkaloids, tbeir salts, denvatives and compounds,
coca leaves, tbeir alkaloids denvatives, extracts
and compounds, niependine, its salts, com
pounds and preparations, and opiates, tbeir
salts, denvatives and compounds.
Medical practitioners' presenpUons for
narcotics is Class B may be accepted by the
pharmacist orally or by telephone and no
signature is required Tlie prescnptioas are
filed on the narcouc file and the label of the
finished product must have the same informa-
lion as Oass A narcouc presenpUons
Oass B narcoUcs include the following sub-
stances and any of their salts
1 Isoquinolme alkaloids of opium (papav
enne, ooscapine, and narceine)
2 Apomorphine
3 Nalorphine
4 (a) Methylmoiphine (codeine) with one
or more active, non narcotic ingredients in tber
apeuUc amounts where the codeine content does
not exceed 8 grams per fluid ounce or I gram
per dosage unit such as ^npinn. Compound
with Codeme, Ednsal with Codeine, Trjgesic
with Codeine
(b) Compounds of codeme with equal or
greater quantity of isoqumolme alkaloid where
the codeine content does not exceed 8 grains
per fluid once or 1 gram per dosage unit
(Copavm)
5 (a) Compoundsofdihydrocodejnonewith
one or more acuve non narcotic ingredients in
therapeutic amounts where the dibydrocodc-
iQone content does not exceed VA grains per
flmdounce or Vc gram per dosage unit (Tus
sionex)
28 The Prescnphon
(b) Compounds of ddiydrocodcinone wilh
a fourfold quantity of any uoquinohne atkatp iH
where the dihydrocodemooe does not exceed
1V6 grams per fluid ounce or Vi gram per dos*
age unit.
6 Compounds of dihydrocodemone with one
or more active non narcotic medicinal wgredi-
ents in therapeutic amounts where the dihydro*
codeinone does not exceed 8 grams per fluid
once or 1 gram per dosage unit
7 Compounds of dibydrohydroxycodetnone
(Oxycodone, Eucodal) with one or more active
non narcotic ingredients in therapeutic amounts
where the dibydroxycodemone does not exceed
VS gram per fluid ounce or Via gram per dosage
unit
8 Compounds of cthylmorphine (Dioom)
with one or more active non narcotic ingredi*
ents m therapeuuc amounts where the ethyl
morphine content does not exceed IVS grams
per fluid ounce or Vi gram per dosage unit
Gass X narcotic drugs may be dispensed
without presenpUoa but a record of each
transaction must be kept m a registration
book.
Preparations of this group contam lo each
fluid once or avoirdupois ounce, along with
therapeuucally active non narcotic mgr^ents,
not more than 2 grams of opium. Vi gram of
morphine or any of its salts. 1 gram of code*
me or any at its salts or Vi gram of ethylmor*
phmc or any of its salts Also mcluded m Class
X are diphenoxylate preparations in solid forms
cootauung not more than 2 5 mg of dipben*
oxylate and not less than 25 microgiams of
atropme sulfate per dosage unit
Class M narcotic drugs contam one of the
following drugs without limit m quantity, along
with either active or inert non narcotic ingredi-
ents of the type used m medicinal preparations
noscapme, papavenne, narceme, cotarmne and
nalorphme.
COMMOS Law and the
Pharmacist
Besides the Federal Narcotic Act, other
Federal laws govern the quality of drugs, the
handling of caustic poisons and the handling
of alcohol for medicinal purposes
Many responsibilities of the pharmacist
arc controlled by common law The courts
often refer to the degree of care and skill
exercised by the pharmacist and require hun
to conduct his practice with “ordinary care ”
The pharmacist is responsible, for cxamj^c.
for the proper interpretation of the presenp-
tion and the dispensing of a product whic±,
when used acconimg to the directions of the
order, will not prove mjunous or poisonous
to the patient He is responsible for and
should detect therapeutic mcompatibilities
involving overdoses
The pharmacist may be held responsible
for the mistakes of his employees caused by
neglect or mcompetence For this reason,
the owner of a pharmacy should buy liability
insurance to protect bunself to case a d ama ge
suit IS filed as a result of the negligence of
one of his pharmacists
Before a pharmacist can be held liable m
court action, it must appear that he was
negligent m his duties as a pharmacist and
that such negligence was responsible for the
plaintiff’s mjuiy The defense to such accusa-
tion attempts to show that the pharmacist did
exercise ‘ ordinary care,” that the plaintiff
conlnbuled negligence or that the pharma-
cist’s negligence was not the real cause of
m/ury of the plain ti/F
In an Illinois case,* subsutution of a drug
m a prescription was considered as negligence
on the part of the pharmacist The presenp-
tiOQ called for ’ Stronuum Salicylate, Wyatt ”
The pharmacist, because he could not find
Wyatt m his manufacturer’s catalog, dis-
pensed pure stronuum sahcylatc msiead of
the intended “Effervescent Suootium Salicy-
late, Wyeth ” The patient, mjured by exces-
sive quantiUes of strontium sdicylatc, recov-
ered damages from the pharmacy because
the pharmacist did not understand the pre-
scription The court ruled that he should have
consulted the physician for proper mterpreta-
tion of the order.
The pharmacist is guilty of ncgbgencc if
be labels a prescription incorre^y In a
Michigan case,* the pharmacist's label di-
rected the patient to take his prcscnpiion,
Fowler’s solution, m tcaspoonful quantities
instead of 3-drop doses
OW^ERSH^P OF THE PRESCRIPTION
Ownership of the presenpuon has always
been a moot question It is a problem worthy
of consideration at this point because, what-
ever document the pharmacist keeps for filing
purposes, whether it be the ongtnal pre-
senpuon wntten by the physiaan or a copy
Some Legal Aspects of Phormacy 29
of that prescnption, there are certain data —
such as the serial number of the prescnption,
the cost pnce and the sellmg pnce — that the
pharmacist will want to record on it and pre-
serve among his records
The ongmal prescnption is, of course,
more valuable to the pharmacist than is a
copy of a prescnption m the event such a
document is used m court proceedmgs In
the case of Humher V State (1926), 21 Ala
App 378, 108 So 646,* the court declined
to allow the doctor to read what he claimed
was a copy of the prescnption Under the
‘best evidence” rule, the highest degree of
proof possible must be produced and no
evidence shall be received if the court thinVs
that the person offenng it can secure better
In this case, the ongmal prescnption was
considered to be the best authonty as to its
contents and also the highest degree of proof
possible
The on^al prescnption wnlten by a
medical practitioner and given to the patient
IS the patient’s property until he presents it
to a pharmacist for compounding purposes
Then there are vanous factors which deter
mme who the owner may be ’
A patient may subimt his prescription to a
pharmacist for compounduig without asking
the pnce of the finished product Even after
the mcdicme is prepared, the patient has a
right to recover Ins ongmal prescnption if
he refuses to pay the pnce asked for the
medicme or refuses to comply with the terms
the pharmacist has set In the case of White
V McComb City Drug Store, Supreme Court
of Mississippi, 1905, 86 Miss 498, 38 So
739, 4 Ann Cos 518,* ® the court decided
that the apothecary, after compounding a
prescnption and delivering the finished
product, might have the n^t to retain the
ongmal prescnption as a record of his busi-
ness, but that be had no right to retain the
ongmal prescnption m that instance where
the sale of the mcdicme was not completed
because the patient could not or would not
comply with the terms the apothecary had
set If the medicme is not delivered Ihe
pharmacist has no need of the prescnption
as a record of his busmess or as an instru-
ment of evidence Hence, the wntten pre-
scnpiion should be returned to the patient
for w horn it w as wntten.
The ownership of the prescnption is con-
trolled by laws m some states which require
a pharmacist who compounds and dispenses
any medicme on a wntten prescription to
preserve the ongmal prescnption for a
specified length of time (1 to 5 )ears) In
other states, there are no such laws desig-
natmg ownership of the prescnption
Regardless of the existence of such state
laws, a pharmacist who fills a prescnptioa
that contains a drug classed as a narcotic
dnig must retam the ongmal prescnption for
a slated lime The Harrison Narcotic Act
(Federal law) requires a pharmacist who
compounds and dispenses any of the drugs
covered by the act (namely, opium, coca
leaves and their denvatives and compounds)
to preserve the ongmal prescnption on file
for a penod of at least 2 years from the date
on which It was compounded The pharma-
cist is the legal custodian of such presenp-
lions, but be cannot refill any of them law-
fully
If the pharmacist is not required by law
(either Federal or state) to retam the ong-
loal written prescnption, qualified ownership
of the prescnption may be determmed by an
expressed agreement^ between the pharma-
cist and the patient Such an agreement (oral
contract) is often entered mto by the phar-
macist and the patient This problem is pre-
sented most frequently by those persons who
have some unusual prescription, such as one
that may have been written m a foreign
country while that person was on a vacation
or a busmess tnp Perhaps he wishes to keep
the ongmal prescnption as a souvenir of his
tnp If it IS decided that the patient will retam
the ongmal prescription, then the pharmacist
must file a copy Such agreement, of course,
should be entered mto before the prescnp-
tion is compounded
Ownership of the prescnption may be de-
termmed also by implied contract,® provided,
of course, that no laws govern ownership of
the prescnption If, m any giseo community.
It js the prevaihng custom for the pharmacist
to retam the ongmal prescnption, it is as-
sumed that all patients will leave their pre-
scriptions to be filed m the store where they
ha%e their prescriptions compounded On the
other hand, if it is the prcvailmg custom for
the patient to retam the ongmal prescnption.
30 The Prescription
then the pharmacist should retom a copy for
his files Expressed agreement seems to hold
precedence over implied contract, and, m
localities where the latter is the general rule,
the pharmacist and the patient can still deter-
mine ownership of the prescription by ex-
pressed contract
The fact that a physician has devised a
formula for a drug or drugs to be com-
pounded and dispensed m the form of a
mcdicme does not give him exclusive right to
his prescnpuons ‘ Unless he patents it, any
person may use the formula and dispense the
medicme under his own name or a fanciful
name, provided, of course, that the law does
not restnet the sale of the constituents (nar-
cotics, for example) However, he may not
attach the originator’s name to the product
unless he has the author s consent to do so A
pharmacist legally can convert the formula
to his own commercial purposes even with-
out the ongmator’s consent, but there would
be a more pleasant feeling between the two
if the pharmacist first obtamed penmssioo
from the physician to use bis fonnula.
It should not be construed from the fore-
going that counter prescnbmg is to be con-
doned Seiling o^cr the counter a bottle of
cough synip of the pharmacist’s own manu-
facture when It IS called for is no different
from sellmg a commercial brand of cough
syrup, but the pharmacist should not countcr-
presenbe — it is the physician’s duty to diag-
nose and presenbe True, the pharmacist
may use the formulas for ethical o\er the-
counter sales or be may use parts of the
formulas to improve other physicians’ pre-
scriptions The latter use of physicians’
formulas is undoubtedly the more important
of the two The pharmacist can do a great
service to physicians m the correction of in-
compaubihues and the general unprovement
of their formulas
The ownership of the medicine dispensed
m accordance with the terms of a prescnption
passes mto the hands of the pauent when
be pays for the product® If the mcdicme docs
not mclude ingredients the sale of which is
regulated by law, he may use it or dispose of
It by sale or gift If it is a narcouc-conlam-
mg prescnption, he cannot give it away or
sell It, since the medicine is mtended only
for his use
Very few pharmacies refuse to give copies
of prescriptions filled to the person for whom
they were written Such refusal usually is
made at the request of the physician who
wrote the prescnption — the physician wish-
ing to han^e the problems of copies himself
In a Texas case,* Stuart Drug Co v Hirsch,
50 S W 583, It was indicated that the custo-
mer had a qualified nght to the use of the
prescnption after it was deposited with the
pharmacist A pharmacist probably has no
right to give copies to anyone other than the
original purchaser, the prescnbmg physician
and duly authorized officers of the law If a
pharmacist gives a copy of a presenpuon to
a person not entitled to ir, and the act of
giving said copy discloses the fact that the
pauent for whom the presenpUon was
wntten is suffering from a disorder hurtful
to him socially or in his business, the phar-
macut can be held accountable
Occasionally, a person will brmg to a
pharmacist a container bcarmg a presenpuon
number and a label from another dmgstore,
with the regucsi that the prescription be
filled by the second pharmacist In most m*
stances, it is possible for the pharmacist to
obtam a copy of the presenpuon from the
first store merely by telephoning for it Of
course, the nature of the drugs prescribed
must be such that (1) refills arc not re-
stneted by law or (2) it is possible to obtam
the pcnmssion of the presenber to refill the
order
REFERE^CES
1 Arthur, W R. The Law of Drugs and
Druggists SL Paul, West, 1955
2 Bureau of Legal Mcdicme and Legislation
Ownership of prescnptions, J AMA 109
19B, 1937
3 O Connell, C L., and Pettit, William A
Manual on PbarmaceuUcal l^w, Philadel
pbia, Lca&Fcbiger, 1938
4 Morrell, C A , and Ordway, E. M The
capacity and vanability of teaspoons, Drug
Standards22 216,1954
5 Muldoon, H C PharmaccuUcat Laun,
New York, Wiley, 1946
C/iapfer 2
BiopharmaceuHcal Considerations in
Dosage Form Design and Evaluation
Gerhard Levy, Pharm. D.*
What IS meant by “dosage form”? In the
narrow sense, it refers to the gross physical
form m whidi a drug is administered to or
used by a patient tablet, capsule, powder,
solution, suspension, ointment, aerosol, etc
The term will be used here m a more compre-
hensive manner to include also dosage form
diaractenstics such as particle size, salt form,
solvent type and dissolution rate, as well as
consideration of effects due to additives
These additives may be pharmacologically
inert m the amounts used (tablet fillers and
lubricants, preservatives, stabilizing agents),
or they may have the function of modifying
the absorption, the biotransformation, or the
excretion of the primary therapeutic agent
Assessment of the desirable or undesirable
effects of a dosage form on the therapeutic
efficacy of the active ingredient and develop-
ment of superior dosage forms lequue con-
sideration of many physical, chemical and
biologic factors The utilization of knowl-
edge and technics derived from such diverse
disciplines as physics, chemistry, mathe-
matics, physical chemistry, physiology, bio-
chemistry, pharmacology and pharmaceutical
technology toward the development and the
evaluation of pharmaceutical formulations
and dosage forms is embodied m a new area
of knowledge and research named biophai-
maceutics Such a far reachmg and inclusive
subject can hardly be covered m detail withm
one chapter, and it is intended here only to
present an overview Much additional nffor-
* Associate Professor of Pharmacy and Biopbar
cnaceuUcs, School of Pharmacy, State Uuvmity of
New York at Buffafo
mation and stimulation can be obtamed by
reading the papers cited as references, and
m particular the reviews by Wagner,^*'*
Nelson,^** Harper,’® Bousquet,^® and Lazarus
and Cooper The biopharmaceutical ap-
proach to pharmaceutical problems is char-
acterized by simultaneous consideration of
both physicochemical and biologic factors
and recognizes tbeir mteraction The reader
should guard against compartmentalized
thinking and, rather, draw on the totahty of
his previously acquired knowledge and apply
it to the present subject. The discussion to
follow will be concerned mainly with oral
dosage forms excludmg sustamed release
medication (which is considered m CHiap-
tcr 3), but many of the factors described
here are also applicable to dosage forms ad-
ministered by other than the oral route.
INTRODUCTION
The therapeutic efficacy of a drug is not
due solely to its inherent chemical constitu-
tion nor IS the qualify of a compounded pie-
senpUon necessarily reflected only by its
elegance and lack of visible signs of incom-
patibihfy The pharmacologic effect elicited
by a therapeutic agent is influenced and
modified by the physical form m which it is
administered, by the nature and the concen-
tration of vanous additives used as pharma-
ceutical formulation aids and by the physico-
chemical and pharmacologic properties of
Qtlur drugs with which it may be combined.
Important and potentially hfe-savmg drugs
may be rendered practically useless by poor
32 Dosage Form Destgn and Evoluotion
formulation PrescnpUons compounded con-
scientiously by phannacjsts who are unaware
of the adverse effect of certain pharmaceuti-
cal manipulations may fail to elicit the ex-
pected therapeutic results
Rccogmtion of the importance of proper
pharmaceutical formulation and the role of
the dosage form m therapeutics has only
evolved in recent years The modem phar-
macist must become thoroughly familiar with
the subject if he is to fulfill his proper func-
tion as a member of the health team Re-
search directed toward acquiring greater
understandmg and additional knowledge of
this field has become an important and ex-
citmg new frontier of pharmacy
KINETICS OF DRUG ABSORPTION
AND ELIMINATION
The mtcnsily of the pharmacologic effect
elicited by a drug is usually some function
of the concentration of this drug at ns site
of action m the body In general, it is not
possible to measure drug coocentratioo at
this site, but a relative measure as well as an
indication of the change of concentration
With time can often be obtained by detemun-
ing the concentration of drug in the blood
as a function of time after drug adraimstra-
tion After a drug has entered the blood-
stream, It diffuses to other fluids of distribu-
tion (lymph, spinal fluid, etc ), organs and
ussues Diffusion equilibnum is usually
reached fairly rapidly and, from then on, any
change in drag concentration in the blood
IS mdicative of concentration changes of dif-
/tiSiWe drug la other tissues Despite certain
complications which may ansc due to drug
bmdmg and slow back iffusioa from some
sites, it has been found that the drug con-
centration m the blood reflects the micusity
of the pharmacologic effect of many thera-
peutic agents It is appropriate, therefore, to
consider the various processes which affect
the direction and the magmtude of the con-
centration changes of drug m the blood
The transfer of a drug from the site of
absorpuon to the bloodstream and from there
to other body tissues, and its subsequent bio-
transformation and excretion can be repre-
sented schematically by the diagram shown
in Figure 14 This scheme is simplified con-
siderably, since U should be noted that each
process depicted by an arrow is actually a
senes of consecutive processes However,
each series may be represented as one over-
all process Furtlicrmorc, some of the single
arrows which mdicate a unidirectional, irre-
versible process actually should be replaced
by a pair of arrows pomting m opposite direc-
tions to reflect the reversibility of these proc-
esses The single arrows are used where the
transfer of drug occurs solely or predomi-
nantly in one direcuon, so that transfer in
the opposite direction may be neglected
The transfer of most drugs across biologic
membranes occurs by passive diffusion from
a region of higher concentration to a region
of lower drug concentration Pick’s law of
diffusion relates diffusion rate to the concen-
tration gradient across the real or the imagi-
nary boundary between two regions m the
following manner
da
( 1 )
where da/dt is the diffusion rale across a
plane of area A, which is perpendicular to
the direction of diffusion, dD/dx is the con-
centration gradient and Kd is a proportional-
ly constant known as the coe^cient of dif-
fusion The negative sign on the right side of
the equation indicates that the drug is diffus-
ing from a region of high concentration to
one of lower concentration Thus the con-
centration gradient is negative in the direc-
tion m which diffusion proceeds • The con-
centration gradient may be expressed as
(D— D|)/(X — Xi>, where D and Di refer
to drug coDcentraaoQ on the high and the low
ooiKealrstioa sides of the aiembranc, re-
spectively, and (X — X:) indicates the dis-
t^ce between the two regions Then,
da
dt
(la)
In the case of many diffusion processes oc-
currmg m the body, this relationship may be
simplified by incorporating the area term A
and the distance expression (X — Xj) in the
proportionality constant Furthermore, the
concentration gradient expression (D — Di)
may be replaced by D, the term represent-
* Actually, dilTuuoa occurs in both directions.
We are concerned here with net dilTusion, where
diHiision rale in one direction is grcaler than in the
other
Kinetics of Drug Absorption and Elimination 33
Drug at
absorption site
Drug m bloodstream
Kil Ik^
Drug excreted m
the urme
Drug excreted by
other routes
Drug m other fluids
of distribution and — ■ ^ . » Biotransfonued drug
Ussues
Fig 14 Schematic representation of drug disposition after absorption (The rate constant
K 5 represents processes occumng primarily in the liver )
mg drug concentration m the region from
which diffusion is takmg place The latter
simplification is justified when the drug con-
centration m the region of lower concentra-
tion (i e , the region toward which diffusion
IS taking place) is very low and negligible
compared with the concentration m the re-
gion from which diffusion occurs TTic sim-
plified equation then takes the form
where O is the drug concentration la the
region from which diffusion is takmg place
and Kt IS a proportionality or rate constant
Equauon ( 2 ) mdicates that the diffusion or
transfer rate is proportional to the concen-
tration of drug at the onginatmg site In
kinetic terms, this is a first-order rate process
as opposed to a zero-order rate process
(where the rate is constant and independent
of concentration) In the discussion to fol-
low, all the processes depicted m Figure 14
by arrows are considered to be first order
processes, and the K’s with various sub-
scripts are the first-order rate constants for
the mdicated processes This means that not
only rates of transfer, but also rates of other
processes, such as biotransformation, are
considered to be proportional to concentra-
tion Such is the case with many drugs when
administered m therapeutic dosage *** In
such cncumstances a generalized considera-
tion of drug absorption and elinunation is
feasible
Apparent Volume of Distribution, The
vanous fluids of distribution, tissues, ^ands
and organs of the body may be considered
as real or imagmary bony compartments and
will be referred to as such At diffusion equi-
hbnum, the concentration of an administered
drug is not the same throughout the body
There may be compartments mto which the
drug may not be able to penetrate and other
compartments with high affimty and bmdmg
capacity for the drug, where drug concentra-
tion IS very high 'rte drug concentration in
the blood reflects these factors It will be
relatively bgh if the drug cannot penetrate
mto a Dum^r of body compartments and
low if certain body compartments have a
high affimty for the drug The distribution of
a drug between the blood and the rest of
the body compartments at equihbnum is re-
flected by Its apparent volume of distribu-
tion
where is the apparent volume of distribu-
tion, Dt, the concentration of drug m the
blood, and as the total amount of drug m
the body (exclusive of the gastromtestmal
tract and the bladder) at the time Db was
measured Knowing Vb, which is a character-
istic property of the drug, under defined con-
ditions, It IS possible to determme the total
drug content of the body by measuring drug
concentration m the blood, since equation
(3) may be re-arranged as follows
= Vb Db (4)
It IS important to realize that this relation-
ship holds true only dunng diffusion equi-
libnum.* The apparent volume of distribu-
Uoa docs not represent the volume of body
space actually containing drug Rather, it is
an apparent value which reflects the distribu-
tion of drug between the blood and the rest
♦This equilibniiia is only appareat, but u per
nuts detemuoatioos of values suitable for practical
puiposes.
34 Dosage Form Design and Evaluaiion
HOURS
Fio IS Average theopbylliae blood
levels for 1 1 human subjects rccciviog 0^
Cm of ammopbyllme by rapid intrave*
nous injection (O) and 1 subject receiving
OS Gm of aminophyUine orally (X)
(From Swintosky, J V Illustrauons and
pharmaceutical interprctatioos of first
order drug elimination rate from the
bloodstream, J Am. Pharm Ass Set Ed
45 395)
of the body, and permits calculation of tranS'
fer rates on the basis of drug cooccntration
changes m the blood
Changes m Body Drug Content and Drug
Coaceatealioa la the BIcad. Re!ecnn§ sgsat
to Figure 14, it con be seen that any change
in body drug content is due to the relative
magnitude of absorption rate, on the one
hand, and excretion and biotiansformation
rates, on the other The excretion and the
biotransformation processes designated by
the rate constants 1^, and Ks may be cod«
sidcrcd together as one elimination process
with a first-order rate constant K« where
daj, _ da^ dap
dt “ dt dt
(6)
where das represents the change m amount
of drug m the body dunng time interval dt,
da^/dt is the absorption rate, and da^/dt is
the elimination rate This may be related to
the drug concentration changes in the blood
by making use of ec^uation (4), substituting
for an and transposmg the term Vb to the
right side of the resultmg equation
dDb _ / da^ dap \ 1
“dt ^"dt dT
(7)
Accordingly, the drug concentration m the
blood, as well as the total amount of drug in
the body, increases when absorption rate is
higher than elimmation rate, decreases when
eliminaiiOQ rate is higher than absorption
rate and remains the same (dDb/dt =: O)
when the absoiption and the chmination
rates arc equal The latter consideration is
the basis of sustained release medication,
where the dosage form is designed to release
initially, and permit the rapid absorption of,
an amount of drug which is sufficient to exert
the desired pharmacologic effect and then
to release slowly addmonal drug so as to
bring about absorption at a rate which is just
sufficient to replace the amount of drug being
eliminated from the body
When a drug is admmistcrcd by rapid in<
travenous injection, the maximum concentra-
tion m the blood is reached at once and
begins immediately to decline, while upon
or^ admmistration drug levels first increase,
reach a peak and then decrease This is illus-
trated in Figure 15, which shov,s hfood levels
of ihconhyllme after oral and after intrave-
nous administration It should be noted that
the peak concentration after oral adrmnistra-
Uon IS considerably lower than after mtravc-
nous injection of an equal dose
After the absorption process has been
completed, the drug disappears from the body
al a rate reflected by the first-order rale con-
stant of elimination, K,, as shown
K* — Kj + K 4 -h Kj (5)
The rate of change of body drug content is
equal to the rate of absorption minus the
rate of elimination, which may be expressed
m the language of calculus as
= (8)
dt
where the negative sign uidicatcs that body
drug content is dccrcasmg with time As aa
dccmascs, the rale of decrease also dumn-
Kiaehcs of Drug Absorption and Elimination 35
ishes, but the fraction of drug elimmated in
a given time period remains constant The
elimmation rate of theophyllme as indicated
by the data shown m Figure 15 can be de-
scribed by the elimination rate constant
Ke = 0 23 hrs This means that the elimi-
nation rale at time t is 23 per cent of the
amount of drug m the body at that time, per
hour Figure 15 actually represents drug
concentration changes m the blood rather
than changes m amount of drug m the body
By substitutmg V^Db for an (equation (4) )
in equation (8) and dividmg each side by
Vb the expression
is obtained ITus shows that the rate of
decime of drug concentration m the blood
(after absorption has been completed) is
proportional to concentration, just as the
rate of decime in total body content of drug
at tune t is proportional to the amount of
drug m the body at that time The urinary
excretion cate of the drug can be related
similarly to K« and Dt, by mcorporatmg
and a factor f which reflects the fraction of
the total amount of drug eventually elimi-
nated by urmaiy excretion without prior bio-
transformation'*^)
fe=K.V,!D» <W)
dt
Integration of equation (9) results in
IogD» = logD,- (II)
where Db is the drug concentration m the
blood at tone t, K, is the elimination rate
constant (m ton©-*) and Do is a constant •
In theoretic terms. Do is the hypotheuc drug
concentration m the blood immediately after
drug admmistration, if absorption and equi-
libration with other tissues were to be m-
stantaneous and no elimmation bad occurred
It can be seen from equation (11) that when
the loganihm of Di, is plotted against t, a
straight line with a slope of — 1^/2 303 is
obtained after absorption is complete This is
* Log D. u (he mtercept on the concealraUon
axis at zero tune upon extrapolation of the Lsear
portion of the tlcsceoding blcxM coocentration curve
when log D» is plotted as a function of bme after
intravenous admiiustratioa. (See Fig. 16 )
FiG 16 Schematic representation of
drug coDcestiatjon changes as a function
of time after oral admirustratton Symbols
are explained m the text (D« ordinarily
should be determmed from blood levels
obtamed after intravenous administration
of drug and is shown here only for illus-
trative purposes )
the reason why blood level data are presented
advantageously m the form of semiloga-
nlhmic graphs whenever chmuiaUQa rate is
proportional to drug concentration Hie
value of Do can be employed to determine
Vb, smcc
,, _ Dose of drug
Do
( 12 )
From equation (11) it can be deduced that
. 0 693
TC
(13)
where t) is the biologic half-Ufe of the drug
(the tune required for a given drug concen-
tration to be decreased by 50%). This value
can be obtained experimentally from blood
level data after absorption has been com-
pleted (Fig 16), and from it K, may be cal-
culated by use of equation (13) Considera-
tion of biologic half-life is of importance m
estabhshmg a proper dosage schedule such
36 Do»3ge Form Des gn ond Evaluation
Fic 17 Schematic representation of
blood levels obtained after oral admiirn
tratiOQ of equal amounts of a drug m
three conventional dosage forms with dif
ferent release charactenstics
that neither drug accumulation to the point
of toxicity nor periods when drug levels are
below the nunimum required for effective
therapy will occur
The absorption, the distribution, and the
elimination of a drug can therefore be char*
actenzed by the parameters K«, and
or tj, respectively The values of these pa*
rameters differ not only between drugs but
also to some degree between individuals For
a gnen drug administered under defined coo-
ditions, It 1 $ possible to establish average
values subject to the usual biologic vana*
tions
One now may identify certain factors
which can affect the concentration of a drug
at Its site of action and thus modify the m
tensity and duration of the pharmacologic
effect elicited by it These arc pnraardy rates
of absorption, excretion and biotransfonna-
tion and the nature of the distribution equi-
librium between the site of action and other
body compartments How these character-
istics may be modified quantitatively by vari-
ous phjsiologic, pharmacologic and ph)sico-
chemical factors will be discussed in the
followmg sections
A more extensive review of the kinetics
of drug absorption, distribution, biolrans-
fonnation and excretion is that by Nelson ***
The application of kinetic coosidcratioos to
the study of a given drug and to the design
of dosage forms is exemplified m a senes of
papers by Swmtosky and co-workcrs“«
Lb m lu
EFFECT OF ABSORPTION RATE
ON DRUG ACnON
iVhen dosage form properties account for
some modification of ^e pharmacologic ac-
tivity of a therapeutic agent, the reason is
most commonly that the inherent absorption
pattern of the drug has been altered to some
extent Therefore, it is appropnate to con-
sider m some det^ the effect of changes m
absorption rate on pharmacologic activity
R^rc 17 represents in schematic fonn the
drug concentration m the blood as a function
of time after oral admmistration of a given
amount of drug m three different dosage
forms These dosage forms, designated A, B
and C, cause the drug to be absorbed at
different rates The resulting drug concentra-
tion vs time patterns will serve to illustrate
the modifications m pharmacologic activity
which may be brought about when a drug is
absorbed at different rates
A therapeutic agent usually must attam
some mmunum conceotratioo at its site or
sites of action before it elicits a given phar-
macologic response At diffusion equilibrium,
there is frequently a corresponding minimum
drug concentration in the blood which ts re-
fer^ to as the ' therapeutic blood level” or
the minimum cffecuve concentration ' of the
drug for a specified therapeutic purpose
Su<± a concentration is indicated in Rgure
17 by a suppled horizontal line Smcc the
onset oj therapeutic ocfivity occurs at the
tunc the drug concentrauon has reached this
level. It IS apparent that a therapeuUc effect
IS elicited most rapidly upon admimsiration
of dosage form A A longer time is required
to obtam a similar effect when the dng ts
administered m dosage form B, while absorp-
tion from dosage form C is so inadequate
that the drug conceotraUon never reaches the
level of effectiveness It is evident that dosage
form A would be the one of choice when
rapid onset of therapeutic effect is desired —
for example, in the case of analgesics On the
other hand, dosage form C is so poorly for-
mulated that ordmanly it must be considered
to be unacceptable as a medicinal prepara-
uon
nic intensity of the pharmacologic effect
IS usually some funcUon of drug concentra-
Effect of Absorption Role on Drug Action 37
tion Thus, the higher peak concentration of
drug when administered m dosage form A
generally will be accompanied by a mote in-
tensive pharmacologic response than that
obtained after admmistraUon of the drug m
dosage form B ^Vhen the peak concMilra-
tion due to A is sufficiently high to cause
undesirable systemic side-reactions or toxic
effects. It may be preferable to use a dosage
form yieldmg the absorption pattern of B
Alternatively, a lower dose of drug may be
admmistered m dosage form A with the pos-
sible added advantage over B of a more rapid
onset of action
The higher the maximum or peak concen-
tration, the longer will be the time required
for the drug concentration to decline to a
subtherapeutic level The duration of the
pharmacologic effect frequently is reflected
by the length of time dunng which the drug
concentration m the blood is equal to or
higher than the minimum effective concen-
tration When this is the case, dosage form A
will brmg about a longer duration of pharma-
cologic activity than dosage fonn B
The total amount of drug absorbed may
be ascertamed by measurmg the area under
the drug concentration vs time curve
The areas under the curves for dosage forms
A and B, respectively, are about equal This
means that although the drug is more rapidly
absorbed when admmistered m dosage form
A, the total amount absorbed is the same
With both dosage forms The area under the
concentration versus tune curve obtained
after administration of the drug m dosage
form C IS about 60 per cent smaller than
the area under the other two curves Assum
mg that the drug is completely absorbed when
administered m dosage form A or B, it may
be stated that the biologic availability of the
drug uben admmistered m dosage form C
IS only 40 per cent The absorption rate is
so low in the latter case that, evidently, 60 per
cent of the drug is propelled past the absorp-
tion sites and excreted m the feces before it
can be absorbed
Faulty formulation of dosage forms result-
ing m reduced biologic availability of the
active constituents is a senous problem be-
cause It may cause patients to be under-
medicated on a dosage regimen thou^t to
Fig 18 Plasma levels of phenyhn-
danedione following administration of 0 4
Gra in two types of tablets (after Schulert,
A R . and Weiner, M The physiologic
disposition of phenylindanedtone in mao,
J Pharmacol Exp Tber 110 451)
be adequate by the physician who prescribed
It A number of reports concerning incom-
plete biologic availabihiy of drugs due to
poor formulation have appeared m the lit-
erature Some of these mvolve very potent
substances, such as anticoagulants, and other
drugs that are used to treat senous diseases,
such as tuberculosis Figure 18 shows differ-
ences m blood levels after administration of
equal doses of phenylmdanedvone in two
different tablet preparations A patient re-
quiring anticoagulant therapy after a stroke,
on switching from one tablet preparation to
the other, either could be subject to senous
hemorrhages due to overdosage, or could be
exposed to the danger of further infarctions
because of inadequate lowenog of prothrom-
bm levels Similar formulation problems have
occurred with the anticoagulants dicuma-
rol“* and warfann Blood levels of para-
aminosalicylate after admmistration of equal
doses of the tuberculostatic agent sodium
para-aminosalicylate m two different tablet
preparations are shown m Figure 19 and
demonstrate the madequate biologic avaQ-
of this drug from one of these prepa-
rations It must be realized that it is not
38 Dosage Form Design and Evaluation
Fio 19 Blood levels of para amino-
salicylate after admioistrauoa of 12 Gm
of sodium para aminosalicylate in ti^o
types of tablets (after Frostad, S Con
tioued studies in concentration of para*
aminosalicylic acid (PAS) in the blood,
Acta tuberc pneumol scand 41 dS)
sufficient for a dosage form to contain the
labeled amount of drug, it is equally impor-
tant that full biologic availability of the drug
be assured by proper formulation
A number of drugs can cause gastrointes-
tinal irntation such as localized erosions of
the mucosa and hemorrhages, or gastroiotcs-
Unal distress such as nausea, vomiting and
diarrhea Salicylates represent the best docu-
mented example of a drug capable of contact
imlation,*^’ but there are other medicinal
agents which appear to have similar liabil-
ities Tctracyclmes have a selective m-
hibitory cHect on certain micro-organisms
usually found m the mtcstinal tract and, there-
fore, can disturb the normal balance of the
microbial flora The resulting overgrowth of
certain molds and fungi may cause nausea,
vomiting, pruritus am and diarrhea It is de-
sirable &at such antibiotics be as completely
absorbed as possible so that there is not a
arge unabsorbed portion m the large bowel,
iccausc the mcidcnce and the seventy of
ocal siJe-effects caused by them is usually
iroportional to the concentration of the drugs
m the large bowel Accordingly, prompt ab-
soiption will tend to dimmish these side
effects while slow and incomplete absorption
would have the opposite effect
One of the desirable attributes of a phar-
maceutical preparation mtended for oral
admmistration is that it be absorbed m a
consistent and predictable manner, since this
is a necessary prerequisite for obtaming a
reasonably consistent Uierapeutic response
The more rapidly a drug is absorbed from
the gastrointestmal tract, the less likely it is
that physiologic variables such as gastric
emptying rate, mtestmaj motility, diet and pH
cause this drug to be absorbed incompletely
or erratically This is apparent from absorp-
tion studies with sulfadiazine,'*’^ sodium
para-ammosalicylatc®’ and many others
On the other hand, delayed absorption, such
as is encountered with sustamed release
dosage forms, is frequently more erratic'^*
and sometimes incomplete ' * A possible ex-
ception to this generalization concerns drugs
that are unstable in gastnc fluids It may be
preferable to formulate such drugs in a man-
ner which prevents or retards their dissolu-
tion m the stomach and thereby minimize s
their degradation due to gastnc enzymes or
low pH \Vhj]e It IS evident that usually the
most reliable way of introducing a given
amount of a drug mto the body is the paren-
teral route, the research pharmacist must con-
sider It a challenge to develop oral dosage
forms which approach as much as possible
the reliability of parenteral medication in this
respect
On the basis of this generalized and, of
necessity, ovcrsimpliflcd discussion, it can be
seen that modifications in the inherent ab-
sorption rate of medicinal agents due to
properties of their oral dosage forms can
affect the onset, the iniemity, and the dura-
tion of pharmacologic activity and the inci-
dence and seventy of toxic reactions and
systemic and local sidc-effccts
BIOLOGIC FACTORS
AcsoRPTiov Processes Passive
D iFFUsio'^ vs Active Transport
Most drugs arc absorbed from the gastro-
intcstinal tract by a process of passive diflu-
Biologic Factors 39
Sion, but som& are absorbed by means of an
active transport mechanism. The absorption
of a drug is affected differently by vanous
biologic and physicochemical factors, de-
pending on the type of absorption process
involved Since this must be taken into con-
sideration when designing and evaluating
pharmaceutical dosage forms, a short review
of absorption processes is m order
Passive diffusion refers to the movement
of molecules from a region o! relatively high
concentration to one of lower concentration
It also mcludes the movement of ions from a
region having the same charge to a region
of lesser or opposite charge Absorption by
passive diffusion does not require expendi-
ture of energy by the organism, it is due
entirely to the concentration or the electrical
gradient existing across the membrane which
separates the gastrointestma] lumen from the
surrounding tissues From equation 2 on
page 33 it is apparent that in the case of
passive diffusion, gastroiotestmal absorption
rate is directly proportional to the concen-
tration of drug m the gastrointestinal fluids
This IS true so long as the drug concentration
m the sutiounding tissues and the blood-
stream IS very low compared with that m
gastromtestinal fluids Accordmgly, the per
cent or fraction of drug absorbed per unit
time IS independent of concentration, while
the amount absorbed over a given tune is
directly proportional to mitial concentration
This is one of the cnteria used to establish
whethw absorption is occurring by passwo
diffusion
Apart from the concentration gradient,
diffusion rate depends also on the perme-
abili^ characteristics of the membrane sepa-
rating the two body compartments These arc
reflected in. equation 2 (p 33), by the v^ue
of Kt, all other conditions being equal The
gastrointestinal membrane acts like a lipid
barrier which permits the ready passage of
lipid soluble drugs, but across which large
lipid msoluble substances diffuse only with
difficulty or not at all Smaller lipid insoluble,
but water soluble substances may pass across
the membrane through numerous pores
which arc too small to be seen even with
the aid of the electron microscope, but for
which strong though indirect evidence exists
When absorption occurs by passive diffusion.
the rate of absorption per unit of mucosal
surface area depends mainly on the concen-
tration of the absorbable form of the drug
m gastromtestmal fluids, the rate of diffusion
through gastromtestmal fluids toward the
mucosal surface and the relative permeabil-
ity of the membrane with respect to the drug
These factors are influenced by a number of
dosage form properties which \vill be dis-
cussed m subsequent sections of this chapter
Absorption by active transport is a spe-
cialized process which requires the expendi-
ture of energy The various active transport
processes found m the gastromtestmal tract
are relatively structure specific and serve pn-
marily for the absorption of natural sub-
strates, such as monosaccharides, I^amino
acids, pynmidmes, bile salts and certain vita-
mms However, there is evidence that certam
drugs also may be absorbed by one of these
active transport processes, if iheir chemical
structures are sufficiently similar to that of
the natural substrate The anticancer drug
5 fluorouracil is an example of an actively
transported drug it js similar m structure
to the natural substrate uracil, which is ab-
sorbed by means of the pynmidme transport
system 5-FIuorouraci] is absorbed by the
same specialized process Active transport is
relatively specific not only m terms of chem-
ical structure but also wiib respect to direc-
tion For example, it may function only m
the movement of a substance from the mu-
cosal to the serosal side of the gastromtes-
tinai tract and not m the reverse direction
Absorption by active transport can take
place agamst a concentration gradient, that
IS, from a region of low concentration to one
of higher concentration The process be-
comes saturated at high concentrations of the
substance which is bemg transported, and
one substance can compete with and depress
the absorption of another if both arc trans-
ported by the same process Since active
transport processes consume energy, they
can be inhibited by various metabolic poi-
sons, such as fluonde and dmitrophenol, and
by lack of oxygen Some natural substrates
and drugs can be absoibed by both active
transport and passive diffusion processes
Absorption by the former process is usually
much more rapid at sufficiently low concen-
trations Absorption by passive diffusion bo*
40 Dotage Form Detign ond Evaluation
comes important at concentrations that are
high enough to saturate the active transport
process From the biopbarmaccutical point
of view, It must be recognized that a drug
which can be absorbed by active transport
will be absorbed relatively more rapidly at
low concentration than at higher concentra-
tions where the active process is more or
less saturated and the slouer passive diffu-
sion process predominates Furthermore, m
the case of active transport, dietary condi-
tions can mduence abso^tion rate of drugs
through the competitive effect of natural sub-
strates ingested as part of the normal food
intake
There are some variants of the two mapr
types of transport processes described thus
far Water flux can mcrease the diffusion
rate of a substance across the gastromtestmal
membrane in the same direction, this is
known as solvent drag Some substances are
transported by a process which does not re-
quue energy and cannot take place against
a concentration gradient, but which is sub-
ject to competition by other substances of
similar structure This absorption process ap-
pears to be an active one and is called
pcdtiated transport Another mechanism of
absorption is that of puiocyiosis (“ccU-drink-
ing'’)< ^bere particulate matter such as od
droplets is brought mto the cell by bemg en-
gulKd in a membrane invagmation which is
subsequently pinched off and mo>ed mto the
mterior of the cell
The various absorption and transfer proc-
esses have been reviewed in greater detail by
Laster and Ingclfingcr** and by Schanker
Intercstmg descriptions of cell membrane
permeability characteristics wntlcn m popu-
lar fashion arc those by Holler** and Solo-
mon
Role of Various Regions of t/ie
Gastrointestinal Tract in Absorption
As on mgested drug descends through the
gastrointestinal tract, it encounters different
environments with respect to pH, cnz)’mcs
and fluidity, as well as anatomic regions with
'different surface characteristics All of these
anablcs can affect the rate of absorption of
le drug It has been stated m the previous
ibscction that absorption by passive diffu-
:on across the gastromicstinal membranes is
restneted primarily to hpid soluble drugs and
that the rate of absorption per unit of mu-
cosal surface is proportional to the concen-
tration of the absorbable form of the drug
in gastiDintestinal fluids Accordmgly, weak
acids and weak bases are absorbed predomi-
nantly m lipid-soluble, un lomzed form **
Their rate of absorption depends not on their
total concentration m gastromtestmal fluids
but on the concentration of the absorbable
(un-ionized) species, which, m turn, is a
function of dissociation constant and of the
pH of their unmcdiate environment Thus,
weak acids are readily absorbed from the
stomach, since they exist m essentially un-
tomzed form m the acidic gastne fluids.
Weak bases are largely ionized m gastne
fluids and arc, therefore, absorbed very
slowly or not at all from the stomach Hus
situation IS reversed m the fluids of the small
inlestme which are cither only mildly acidic,
neutral or even somewhat basic Such an
environment favors, relatively speakmg, the
absorption of drugs that are weak bases
Under these circumstances it is apparent that
a weakly acidic drug, when administered in
solid form, must dissolve readily m gastric
fluids if rapid absorption is desired Umortu-
natety, weak acids generally do not dissolve
as rapidly m acidic fluids as do weak bases
The reverse would be much more desirable,
smcc rapid dissolution of weakly basic drugs
in gastne fluids is not as important because
weak bases are not absorbed to any significant
extent from the stomach
It IS cnlightenmg to consider the change
m the degree of ionization of two weak acids,
diffenng m K« value, as they are exposed to
an environment of increasing pH (which
would be the case when they descend through
the gastromtestmal tract) Both substances
essentially arc un ionized at very low pH
and dissoaate to an mcrcasmg degree as
they encounter regions of higher pH The
weaker acid will ionize to a lesser degree at
a given pH than the stronger and, and the
concentration ratio of the un lomzcd (ab-
sorbable) species of the two drugs will m-
crease in favor of the weaker acid at
higher pH
This IS shown m Figure 20 for two weakly
aadic drugs, benzoic acid and salic)lic acid
Jt IS to expected that the wcAer acid
(benzoic acid) is relatively better absorbed
than the stronger acid as the pH increases
This IS indeed the case, as evidenced by the
absoqition data also shown m Figure 20
A more extensive tabulation demonstrates
that this relationship holds also for other
weakly acidic dnigs However, m all in-
stances, the relative mcrease in absorption
rate ratio was not as great as the increase
in the concentration ratio of the tin ionized
form of the two drugs This is probably due
to the fact that the pH at the gastrointesimal
membrane is not necessarily the same as the
pH of the gastrointestinal fiuids, since it has
been found that the mtestmal membrane has
a somewhat acidic zone While this acidic
pH apparently can be modified m either
direction by changing the pH of the gastro-
mtestmal Quids, the magmtude of the mem-
brane pH change is not necessarily the same
as that of the pH change of the gastrointes-
tinal Quids It should be pomted out that m
the mtact animal the small mtestme strongly
resists alteration m the pH of its luminal con-
tents Hence, it is not practical to modify
the pH of mtestmal Qmds under climcal con-
ditions The pH of gastric Quids can be m-
creased by antacids and other suitable alka-
hne substances, and the absorption rate of
weak acids and weak bases can be decreased
and mcreased, respectively, m the human
under these circumstances
While the differences between the pH of
the gastric and the mtestmal Quids account
to some extent for the different rates of ab-
sorption of certam drugs from these two
areas, the mam reason is the difference m the
absorptive surface areas Anatomically, the
small mtestme is much better designed for
absorption than the stomach The mtestmal
mucosa is covered by numerous vilh and
provides a very large surface for absorp-
tion The ratio of mucosal surface area/
serosal surface area (MA/SA) is hipest in
the proximal region of the small mtestme and
decreases toward the more distal regions
MA/SA ratios of the upper, the middle and
the Iol^er segments of the rat small intestine
are 113, 9 8 and 4 3, respectively" It is
known that the decrease m MA/SA ratio as
one descends the human mtestme is also
rather large.*®® Furthermore, the electrical
potential across the small mtestme, which is
1 2 S 4 5 6 7
Fig 30 Change m the ratio of un ion
ized benzoic acid (pK. s 4 2) to un ion
ized salicylic acid (pk« = 3 0) and m the
ratio of their absorption rates from the
gastromtestmal tract of the rat, as a fuoc
HOD of pH (assuming equimolar concen-
tration of total drug) Absorption data
from Schanker, h.S ,etal J Pharmacol
Exp Ther i20 528, and Hogben, C A
M , et al ) Pharmacol Exp Ther 125
275
positive on the serosal side, is higher m the
jejunum than in the ileum The pH of the
intestinal fluids also mcreases m the distal
direction ** Thus, there exists a duodenal,
jejunal to ileal gradient with respect to ab-
sorptive surface area (MA/SA), electncal
gradient and pH The large mtestme presents
much less favorable anatomic condiuons for
absorption a larger lumen and no villi The
effect of the latter will be appreciated by the
fact that the presence of viUi m the human
small mtestme increases the surface area
from seven to ei^teen times over what it
would be without viUi
Most of the water absorption from the
gastromtestmal tract occurs m the small m-
teslinc ** As the gastiomieslinal content
passes through the small mtestme, it changes
hrom Quid to pasty consisteni^ Drug solids
42 Dosage Form Design and Evaluaiion
which ha\e not been dissolved in the stem*
acb or the small intestme may not encounter
sufficient fluids for dissolution m the large
mtcstine Diffusion of dissolved drug to the
mtestjnal mucosa also is bmdered by the m*
spissation (thickening) of the contents of the
large intestme Thus pH, surface area, avail*
ability of aqueous fluids to dissolve mgested
drug solids and consistency of intestmal con-
tents are some of the factors which differ in
various regions of the gastromtestinal tract.
They can account for differences in the ab-
sorption rate of a drug from these regions
The existence of optimal regions for ab-
serpUoa js even more clear-cut wjlh respect
to substances that are absorbed by means of
an active transport mechanism It has been
established that iron absorption occurs
mainly in the proximal part of the small m-
testme and decreases progressively m the
more distal mteslinal segments, s* while
the absorption of bile salts is limited to the
dutal deal segment Riboflavin apparently
is absorbed only from the upper regions of
the and thiamine absorption also
occurs mainly m the proximal regions Under
equal conditions of supply, the ^sorption of
thiamine m the distal sections of the intes-
tine is only 20 per cent of that found m the
proximal sections The site of active vita-
mm Bis absorption in man is the ilcum,
and there may be a specific vitamm Bi-
receptor mechanism m this part of the
small intestme The colon apparently
lacks certam specific transport processes
present in some or all of the regions of the
small mtcstine, namely, those for glucose and
galactose, L-tyrosme, and vitamin Bis " “Hus
suggests that the rectal route of adrrunistra
tion IS not satisfactory for substances which
arc absorbed by one of several active trans-
port processes
The existence of specialized absorption
sites and regional differences with respect to
pH, surface area and other properties in the
gastromtestinal tract implies that orally ad-
mmisicrcd drugs should be m physiologically
available form (for example, in solution
rather than in solid form) by the time they
reach their respective optimum absorption
sues Only limited time is available for the
dissolution of a solid medicament, the modi-
fication of an unabsorbablc molecule to an
absorbable one by hydrolysis, and similar
transformations of drugs to their physiologi-
cally avadable forms in the gastromtestinal
tract, especially if the optimum absorption
Site is the proximal section of the small m-
tesune The rate of passage of intestinal con-
tents through the upper small mtcstme is
higher than it is through the lower part For
example, it has been found that the transit
time of a balloon through the duodenum is
5 mmutes, through the jejunum, 2 hours, and
through the ileum, 3 to 6 hours Drugs that
are not m absorbable form within indicated
tunc limits may be propelled past their ab-
soipuoa sites and excreted totally or m part
m the feces
Gastric Emptying Rate
In view of the quabtative and the quanti-
tative differences bctucen the absorption
properties of the stomach and the mtcstme,
any delay m the transfer of a drug from stom-
ach to intestine may affect absorption rate
and, thereby, the onset of therapeutic activ-
ity For instance, a weak base such as
cwine Will be absorbed primarily from the
smalt intestme rather than from the stomach,
and any delay m gastric emptying will tend
to delay the onset of analgesia Slow gastric
emptymg can also affect die biologic avail-
abili^ of drugs that are unstable m gastnc
fluids, the extent of degradation being pro-
portional to the tune durmg which such drugs
arc exposed to low pH or gastric enzymes
The effect of pharmaceutical formulation
variables on the dissolution rate of weakly
acidic drugs usually will be most noticeable
while the drugs are m the stomach, where
ordraarily they dissolve rclaiivcly slowly
Such differences tend to disappear when the
drugs reach the small mtcstme, where disso-
lution IS usually more rapid and less affected
by differences m dosage form properties
Consequently, the results of absorption
studies and certam other types of clinical
evaluations, both comparative and absolute,
can be affected by the gastnc emptymg rale
of the experimental subjects This is one rea-
son why absorption studies often yield more
consistent results when earned out on fasted
subjects Type of food, volume, osmotic
pressure, pH and buffer capacity, tempera-
ture and viscosity of gastnc contents, age
Biologic Factors 43
and state of health of the subjects and en-
vironmental circumstances dunng the study
are typical factors which can influence gastric
emptying rate Gastnc content leaves die
stomach by a first-order process, le, at a
rate which is proportional to volume With
small volumes, there is an mitial lag time
before gastnc emptymg begms, while with
higher volumes there is an mitial phase of
more rapid emptying Thus, mgestion of
large volumes of hquid may favor drug ab-
sorption by mcreasmg the mitial rate of
transfer of drug to the small mtestine Liquids
of low viscosity are emptied more rapidly
than liquids of high viscosity Solutions or
suspensions of fine particles leave the stom-
ach at a higher rate than lumpy substances
Hence, enteric coated tablets, which do not
dismtegrate in gastnc fluids, often remam m
the stomach for a considerable length of
time^ Liquids havmg a high osmotic pres-
sure are emptied more slowly than pure
water or solutions of lower osmotic pressure
Fats slow gastnc emptying rate considerably,
protems have a lesser effect, and starch re-
tards gastnc emptying the least Gastnc
emptymg also is retarded by increased acidity
of the duodenal contents, which, in turn, is
related to the acidity of the gastric fluids
It has been found that subjects with duodenal
ulcers and gastnc hyperacidity have a higher
gastnc emptymg rate than healthy subjects,
while those suffering from gastnc achylia
have a lower emptying rate **
A number of drags are capable of affect-
ing gastric emptymg rate, usually by some
central mechanism but, in some instances, ap-
parently by means of a local effect. Aspitm,
morphine and codeine are among those drugs
which delay gastnc emptymg Posture
also can affect the rate of gastnc emptymg
For certain individuals, gastnc emptymg is
facilitated by lying on the nght side and de-
layed by lymg m supine position^* Since
gastric emptymg can be a major hnutmg
factor With respect to the rate of absorption
of certain drugs, it will be appreciated that
the variables described m the prccedmg para-
graphs can have a significant effect on drug
absorption It has been pomted out recently
that It may even make a difference whether
a subject is standmg or sittmg, since this can
affect the rapidity and completeness of ab-
sorption of orally administered drugs Dis-
regard for these considerations could intro-
duce considerable bias m the clmical testmg
and evaluation of dosage forms
Interaction of Drugs with Com-
ponents OF Gastrointestinal Mucosa
Interaction of drugs with substances pres-
ent m or secreted by the gastromtestmal
mucosa can be of considerable consequence
m the absorption of such drugs This may be
illustrated by a consideration of the gastro-
lotestinal absorption of quaternary ammo-
mum compounds, many of which are used as
antichohnergic and hypotensive agents It is
known that many of these drugs are absorbed
poorly and irregularly from the gastrointes-
tmal tract V^e this probably is related
to some extent to their poor lipoid solubihty,
It has been shown that quaternary ammo-
nium compounds form nonabsorbable com-
plexes with polysaccharide acids of intestinal
mucm Once the mechanism for the poor
absorption of quaternaries bad been eluci-
dated, formulauon adjustments to circum-
vent this problem and to facilitate absorption
could be made A physiologically inert
quateraaiy was coadministered, which either
interacted preferentially or competed with the
pharmacologically active quaternary for m-
teracuon sites TTus resulted in less bmding
and greater physiologic availability of the
drug, as shown m both animals and hu-
mans The more complete gasiromtesti-
nol absorption of hypotensive quaternaries
thus attained permitted a reduction of the
administered dose, which is desirable not
oidy for economic reasons but also because
some of these drags exhibit undesirable local
actmns on the gastrointestinal tract ** The
use of pharmacologically inert quaternaries
to enhance drug absorption is not limited to
hypotensives but is also applicable to other
quaternaries such as cholinergics and anti-
spasmodics Of interest with respect to the
previous discussion concerning regions of
optimum absorption m the gastromtestmal
tract IS the observation that the drug mucm
interaction decreases at lower pH It has
been suggested that for this reason absorp-
tion of quatenmnes may be most rapid from
the upper part of the gastromtesunal tract.
Dela^ia drag release from dosage forms
44 Dosoge Form Design and Evaluotion
could, under such circumstances, have sen*
ous consequences One nu^t also speculate
that coadnunistration of antacids could inter*
fere with the absorption of these drugs due
to increased drug binding at higher pH
Along with a consideration of those types
of interactions which cause inhibition of drug
absorption, it is appropriate to mention rnter-
aclions leading to opposite effects Obviously,
this encompasses all instances of active trans*
port, for which the interaction of drug with
a “earner” is often postulated Of
greater interest to biophannaccutics are in-
teractions with compounds which can be iso-
lated and reasonably defined, such as the
well known interaction of vitamm Bi- with
mtnnsic factor and the recently reported
mteracuon of quaternary ammonium com-
pounds with a phospbatido-peptide fraction
of mtcsUnal tissue Smee these physiologic
materials can be isolated, they can be em-
plo>ed as dosage form addiuves to enhance
the absorption of certain dnigs Little pub-
lished work is as yet available m this area,
but It would seem that it represents a unique
and perhaps fruitful approach to improved
drag fonsuIatioQ
OtOTRANSFORMATION AND BIOLOGIC
Half-life
The subject of biotransformauon, which
IS also called detoxication or drug metabo-
lism, IS so extensive as to constitute almost
a separate disciplme It will be discussed here
only m a limited mann er, pnmardy with re-
spect to its relationship to the biologic balf-
lifc or clinunalion rate of drugs More exten-
sive and detailed information can be ob-
tained from the book Detoxication Mecha~
nisnis by R T Williams An excellent and
up-to-date review article on the subject has
also appeared “
Williams-®® has classified the metabohe
changes undergone by drugs and other for-
eign compounds m the body from a pharma-
cologic aspect as follows (1) reactions in
which biologically inactive compounds arc
converted into acuve metabolites, (2) reac-
tions in which biologically active compounds
arc converted mto active metabolites with the
same or different activity, (3) reactions m
which biologically acuve compounds arc con-
verted into macuve metabolites fay oxidation,
reduction or h)drol>sis, (4) detoxication
mediamsms, i e , reactions between foreign
compounds and body carbohydrates or
ammo acids to yield inactive and nontoxic
excretory products, and (5) lethal syntheses,
I e , reactions between the foreign compound
and a body constituent to produce an mjun-
ous product. The discussion to follow will be
concerned primarily with reactions of types
(3) and (4) which involve the conversion
of phaimacobgically active compounds to
essentially mactive metabolites It has already
been pointed out that the elimination rate of
a pharmacologically active compound de-
pends on Its rate of biotransforraation to
inactive metabolites and the rate of excretion
of Its unchanged (active) form The elimi-
nation rate, which ts often expressed m terms
of the biologic half-life of the drug mvoivcd,
dctenjuncs the persistence time of drug pres-
ent m the body The persistence tunc fre-
quently can be related to the duration of
pharmacologic activity
A rational dosage regimen must be based
on a consideration of a drug’s biologic half-
life Too frequent administrauon of addi-
tional (mamtenance) doses after the initial
dose, or mawlcnjocc Joses which are too
high, may cause drug accumulation and toxic
reactions On the other bond, maintenance
doses which are too low or which ore spaced
too far apart result in a decline m the total
amount of drug in the body and may cause
the treatment to be meffective rrcqucnily, it
IS necessary to administer a relatively high
miiial or pnming dose, followed by lower
mamicnaocc doses at appropnatc intervals
The shorter the lime intervals between doses,
the lower is the amount of drug required to
maintain the drug content of the body m the
desired range Furthermore, the magnitude
of the fluctuations of drug concentration in
various body compartments diminishes as the
frequency of administration of appropnatc
maintenance doses increases until, when the
frequen^ becomes mfinitely large (lc , on
continuous adnunistration), (he drug con-
centration in the body remains constant
(assuming the dosage or rale of drug admin-
istration to be correct) Continuous drug
administration can be achieved by intrave-
nous dnp or by means of properly designed
oral sustained release dosage forms
la certam instances it may be possible to
Biologic Factors 45
achieve much better therapeutic results by
continuous drug administration (thereby
maintaining a constant drug concentration
in Quids of distnbution) than are obtained
with penodic drug admmistration and the
associated fluctuations of drug concentration
m the fluids The reader may recall that drug
diffuses from blood to the tissues when the
concentration of drug in diffusible form is
higher m the blood and that drug leaves the
tissues and diffuses back mto the blood when
the concentration gradient is reversed If the
rate of diffusion of a drug to the site of action
is very low,* it may be impossible to achieve
diffusion equiUbnum between the particular
site and the fluids of distnbution la the
course of conventional drug therapy, par-
ticularly if the drug is rapidly eliminated
Under such circumstances it becomes neces-
sary to establish a relatively high drug con-
centration m the bloodstream m order to
attam n considerably lower concentration at
the site of action '^ts may be undesirable,
not only for economic reasons but also be
cause of possible toxic reactions which could
occur, especially when there is a separate
site of action wiA respect to the toxic activity
and when diffusion to that site can occur
quite rapidly On reflection, one is struck by
the question of how many potentially useful
drugs may have been overlooked during a
phannacologic screening process or cimical
tnal because neither biologic half life nor
diffusion problems were taken into consid-
eration adequately in establishing the dosage
schedule It has been reported recently that
the blood supply to cancerous tissue is quite
limited,^’ which suggests that failure of
chemotherapy of malignancies may, in some
instances, be due to an madequacy of the
drug concentration obtained in tumor tissue
Based on considerations outlined m the pre-
ceding paragraphs, it would seem to be ad-
visable to admimster certain anticancer
drugs m a manner which leads to relatively
constant drug levels m the fluids of dis-
tnbution Indeed, it has been observed that
* For example, the rate of diffusioa of sulfa
iliaxme from bloi^ to cerebrospinal fluid is so low
that 6 to 8 hours are required for the coaceatralioo
of drug in cerebrospin^ fluid to reach half the free
drug cooceDlration in blood plasma (under con
ditions where drug plasma concentration is con
Siam) 150
Table 3 Dosage Intervals (T) ano
Ratios of Initial Dose to Maintenance
Dose (D*/D) for Maintaining
Constant Drug Concentration*
Druo
Average
t| (hours) T (hours)
D*/D
Sulfaduazole
35
4
1 8
Sulfisoxazole
61
6
20
Sulfanilamide
88
8
2.1
Acetyl sulfisoxazole 13 1
12
21
Sulfadiazine
167
24
1 6
Sulfamerazioe
23 5
24
20
Sulfadimethoxine
410
24
30
• Part of a tabulation by Kruger Thicmer E.,
and Buoger, P Arzneun Forsch 11 867
administration of the anticancer drug
amethoptenn by contmuous mtraveoous dnp
was more effective than admmistration of the
same amount of drug m a single daily dose
Apparently, this is due to the sustamed drug
levels achieved by the former procedure
How important it is for rational therapy
U> consider the biologic half life of a drug
when establishing its dosage schedule may
be shown m the foUowmg tabulation by
Kruger-Thiemer and Bunger,*-* who calcu-
lated for a number of sulfa drugs the ratio
of mitial dose maintenance dose {D*/D)
and the time intervals (T) between doses
necessary to maintain drug levels m the body
within a constant range (Table 3)
According to the data m Table 3, it is
necessary to admimster one half die mitial
dose of sulfisoxazole every 6 hours to mam-
tain constant body concentration of the drug,
while m the case of sulfadimethoxine one
would give one third the mitial dose every
24 hours The differences m biologic half-
life between the various sulfa drugs were not
gjneraify appreciated m die early days of
sulfonamide therapy, and it has been pointed
out that sulfa drugs with a long half life
(such as sulfadiazine and sulfamcrazine) be-
came discredited because of frequent toxic
reactions These latter were actu^iy due to
too frequent dosage and the resulting drug
accumuhition The combination of two or
more sulfonamides m one dosage form also
has been criticized, smcc most of such com-
binations mvohe substances that differ sig-
nificantly m biologic half life ” Rational
48 Dosage Form Design and Evaluohon
recent review article “ While these proper-
ties of drugs cause problems and complica-
tions iQ chemotherapy, they can be utilized
also m prolongmg the duration of drug action
or in tcrimnaung it more rapidly Vihere nec-
essary This often can be accomplished by
relatively mnocuous substances, such as bio-
Oavmoids and glucuronic acid
Intcrsubject Variation. The biologic half-
life of drugs as reported in the literature
represents an average value for the type of
subject m which it was established However,
even within a group of individuals relatively
standardized with respect to age, state of
health, therapeutic r^imen and similar po-
tential variables, the biologic half life vanes
significantly Such mtcrsubject variation is
as characteristic as that of oUier biologic
parameters, such as weight hei^t and color
of the eyes Kruger-T^emcr and Hunger
found twofold differences in the biologic
half life of each of a number of sulfonamides
in different mdividuals all of whom were
healthy and of similar age These authors
cite similar czpeneoces of other mvesuga-
tors with streptomycin kanamycin, isoniazid
and py/azinamide Another report indicates
eightfold diifcrcoces m rates of metabolism
of dicumarol and eihylbiscumacetate Also,
there may be occasional intrasubjecc vana-
Uons due to changes in dietary habits. Quid
mtakc and physical activity Such variations,
regardless of cause, can represent senous
problems in chemotherapy due to the danger
of undertreatment or drug accumulation and
the attendant toxicities Fortunately, it is
often possible to titrate * patients, using lack
of clinical response and onset of side elTccts
as indicators of underdosage and overdosage,
respectively Such technic may not be useful
with drugs havmg unfavorable therapeutic
ratios or insidious or delayed toxic reactions
Often, It may be dcsuable actually to deter-
mine the biologic half life of a drug m a gnen
patient at the start of therapy and to adjust
the subsequent dosage regimen accordingly
Altemalivcly, it has been suggested that dmly
blood samples be drawn during the course of
therapy just pnor to administration of the
next dose m otticr to establish the muu-
mum concentration of drug m the blood and,
then, to note whether accumulation or con-
centration dcchoe IS occurring m the course
of therapy” These considerations are also
indicative of some serious fundamental limi-
tations of sustained release dosage forms,
since the release charactenstics of such forms
must, of necessity, be based on requirements
related to the half life of a drug m the aver-
age individual Moreover, such dosage forms
permit no adjustments of dosage regimen
other than to increase or decrease the amount
of admmistercd drug, the rate of release or
drug supply to the body (which is analogous
to the frequency of administration of drug
in conventional form) cannot be changed
BiotransfomiatjOQ During Gastromtcstinal
Ahsorplion. Some recent work points to the
gastromtcstmol wail os a site of biotrans-
formation of certain drugs Thus, a drug may
be partially inactivated even before it enters
the Quids of distribution unless, for example,
Its conjugated form is fully hydrolyzed and
reverted to free drug at the serosal side of the
gastrointestinal membrane A consideration
of possible biotransfoimation of drugs during
their gastromtcstinal absorption is therefore
pertiocDt before considering, m a foUowmg
section, the effect of route of administration
on drug aciiviiy
Formation of drug glucuronides, until re-
cently thought to be limited to the liver and
(to a lesser extent) the kidneys, takes place
also m the mucous membranes of the gastro-
mtestmal tract In fact ommal data suggest
Chat s^chcsis of glucuronides m the fetal
stomach is already at the adult level, whereas
hepatic conjugauon with glucuronides is
known to be very low in the newborn ***
Thyroxine, truodothyronme and certam thy-
roxine analogs which arc absorbed by an
active transport process are also changed
to glucuronic acid conjugates during ab-
sorption
Whether biotransformation of drugs m the
gasliDintcsUnal tissues is fully reversible and
pninanly a mechanism for active transmit
(the glucuromdc cannot diffuse back mto
the lumen due to its lipoid msolubility), or
whether it is irreversible in the body and thus
serves as part of the detoxication process,
has not os yet been established In the mean-
time It IS important that the possibility of
biotransformation dunng gastrointcstmal ab-
sorption be considered as one possible cause
for differences between the pboimacologic
Biologic Factors
4;
results obtained from oral and parenteral
dosage fonns, smce drug plasma levels and
therapeutic response after parenteral admin
istration often serve as the standard of com
panson for evaluation of oral dosage forms
Rate of Decline op Pharmacologic
Acnviry
The changes of drug concentration in body
fluids as a function of time need not neces-
sarily parallel pharmacologic activity time re-
lationships For that reason it is desirable
and, often, technically feasible to determine
the change m mtensity of a given pharma-
cologic effect with time For example, re-
serpine has a half life of only 15 minutes,
yet Its pharmacologic effects persist for 36
to 48 hours It has been suggested that the
prolonged effects are due to an irreversible
mactivation of reactive sites on the enzyme
monamme oxidase ** Under such circum-
stances the duration of the pharmacologic
effect may be related to the rate of formation
of new enzyme rather than to the rate of dis-
appearance of drug from the site of action
Coumann type anticoagulants, such as di-
cumarol, require 24 hours or more after even
parenteral administration to cause an m-
crease m prothrombin time, evidently because
of their indirect effect which is exerted on
an early phase of prothrombin synthesis
A dnig may exhibit different activity vs
tune relationships for different pharmaco-
logic effects This is the case with morpbme
and other opiates, which exhibit different
activity ume sequences for analgesia and de-
pression, respectively It is of interest to
note that differences m half-life as a function
of dosage have been observed not only for
drug eliimnation (cf previous section) but
also With respect to the decline of a phar-
macologic response (mydnasis) Differ-
ences between the time sequences of drug
concentration and pharmacologic activi^
must be taken into consideration m pharma-
ceutical formulation If the tuo sequences co-
incide and rapid onset of activity is desired,
it IS desirable to have dosage forms which
permit the drug to be absorbed rapidly On
the other hand, if there is considerable lag
m pharmacologic response, there is little ad-
^tage m rapid drug release from dosage
forms so long as release is not delayed to the
point of causing incomplete absorption Sirni-
admimstration
and the design of sustamed release forms
^y have to be related m certain mstanccs
pharmacologic activity
rather than to that of drug elimmation
Urinary Excretion
It has been explained previously that dnio
elimination is the result of biotransfonna-
tioa and excretion of unchanged drug In
most cases, the urmaiy route is the maior
excrctoy pathway, although some drugs me
excreted primarily m the bde BUiaiy eicie-
tion beimmes an important means of drug
removal from the body only d subsequent
gastromlestinal reabsoiption of a dnig’thus
excreted does not occur to any major degree
Urmary excretion of drugs can mvolve three
processes glomerular filtration, active tubu-
lar excreuon of orgamc acids or bases m
ionic form and passive back diffusion fre-
absoipuon) of part of such acids or bases m
noniomc form from the lower tubular re-
gions Since the rate of reabsorption %
proporUonal to the concentrabon of drug m
un-iomaed form, it is possible to modify this
rate by ebangmg the pH of the unue In this
way one may either mcrease or decrease the
urmary excretion rate and, therefore, the
eb^auon rate of drugs which are weak
acids or weak bases
T^e unnary excretion rate of salicylic acid
can be decreased and higher salicylate blood
levels achieved by acidifying the urme with
a^onium chloride An opposite effect is
flamed by a^mstration of sodium bicar-
bonate, and this technic has been used to
trwt cases of salicylate poisonmg, smce it
thieves rapid removal of the drug from the
body Similarly, Kostenbauder and co-work-
ere have shown that the elimination rate of
the sulfonamide sulfaethidole can be changed
by urmary pH adjustment « When the urine
was mamtamed at a pH of 4 8 to 5 2 the
averagebiologichalf Iifeofthednigwas n 4
n^rs Upon adjustment of urmary oH to
7 9 to 8 1 die half bfe was an
average of only 4 2 hours Sulfaethidole is
a weak acid with a pK. of 5 5. and it may
be calculated that 76 per cent of the drug is
m on ionized fonn at pH 5 0. while oalv
about I 5 per cent is un ionized at pH 7 8
50 Dosage Form Design and Evoluation
The urmaiy excretion of drugs can also
be retarded by administration of agents ca-
pable of mhibitmg their tubular secretion For
example, probenecid prolongs the biologic
half-Ji/e of penicillms by such a media-
nism The state of health, particularly with
respect to kidney function, can be a factor
m the urmaiy excretion of drugs Thus, the
average excretion rate constant for exoge-
nous hippuric acid was found to be 2 7
hours'"^ m normal subjects, but only 1 2
hours”’ m subjects with renal disease
Route of Administration
Quantitative diJIerences m the pbanna-
cologic activity of drugs as a function of route
of admmistration are observed frequently
and can be related usually to differences tn
rates of absorpuon and drug concentration
maxima One ordinarily expects a drug to
have the same qualitative effect regardless
of route of administration, but there is a
sufBcient number of exceptions to justify spe-
cial consideration A case m pomt is mag-
nesium sulfate, which acts as a laxative when
taken orally but is a powerful central nervous
system depressant v.hcn administered paren-
terally The laxative effect and absence of
syTtcmic activity on oral admuustratioo is
due to the very limited absorption of mag-
nesium sulfate from the gastromtcsUnal tract
Drugs that are absorbed from the gastro-
mtcsUnal tract enter the portal circulation
and arc channeled immediately to the liver,
which IS the major site of biotransformation
On the other hand, drugs do not pass direcUy
to the liver when administered porenterally,
sublingually or rcctally Consequently, the
tissue distribution pattern of drugs may differ
considerably, depending on route of admin-
istration This, m turn, can result m the pre-
dominance of one or another pharmacologic
effect Certam monamine oxidase inhibitors,
namely phcniprazine, phenelzine and, to some
extent, isocarboxazid, give nsc to greater
brain monammo oxidase inhibition than liver
monamine oxidase inhibition when adminis-
tered subcutaneously On oral admmistia-
uon, these drugs exert a more pronounced
liver monamine oxidase inhibition than bram
monamine oxidase mhibiuon This is con-
sidered to be due to the drug passing directly
to the brain on subcutaneous adnunislratroo,
while passing first through the liver when
given orally A difference m tissue distribu-
tion pattern as a function of route of admin-
istration has also been observed with gnseo-
fulvm, the drug was concentrated in the lungs
and the skin after intravenous administration
and m liver, skm, skeletal muscle and fat
after oral administration ” Pretreatment with
barbiturates accelerates the elumnation of
orally admmistercd biscoumacetate, but bar-
biturates have no appreciable effect on the
elunmation of mtravenously adnunistcred bis-
coumacetate This suggests differences m the
metabolic pathway of this anticoagulant as
a function of route of administration
The activity ratios between several opiates
vary with different routes of admmistration
This IS also true for the active constituents of
thyroid, namely tniodothyronme and thyrox-
me The latter instance can be related to the
incomplete gastrointestinal absorption of
thyroxine Smee tniodothyronme is well ab-
sorbed, the acDvjty ratio between the two
compounds differs dependmg on route of ad-
ministration
In some instances, the differences in drug
effects associated with different routes of
administration may be related to different
biotransformatiOD patterns as a consequence
of differences in races of absorption In these
cases, similar effects can be observed by ad-
mmistcrmg the drug at different rates by any
one route The metabolism of 5-hydroxy-
tryptamine is thus affected Rapid mtravenous
injection of this compound causes greater
formation of its o-glucuronidc than subcu-
taneous administration or sfow intravenous
infusion ’ The phenolic conjugation of 5-
hydroxytryptamine, therefore, is considered
to be an emergency route for its elimination.
However, the most mlcnse phenolic conjuga-
tion occurs after oral admmistration, despite
the slower rate of drug entry mto the body ^
This may be due to partial conjugation m the
gastromtcsUnal wall, as described m a previ-
ous secUon Opposite rate effects arc found
with respect to the biotransformation of the
anutubercular drug p aminosalicylic acid
This drug is inacUvated pnmanly by acetyla-
tion Administration of a doily dose ui sev-
eral small mcrements causes the greatest de-
gree of acctylauon, while giving the drug m
a single large daily dose causes the least
acetyJation®® probably due to saturation of the
acctylauon process m the body Goose-
Btotogic Focfors
51
quently, the use of single daily doses is pre-
ferred and considered to be more effective
The hormonal activity of A*-3 ketosleroids
IS affected m a paradoxical manner by cnol
etherification parenteral activity is decreased
while oral effectiveness is increased “ The
mvestigators feel that this is due to differ-
ences in biotransformation, but it has also
been suggested that differences m rates of
hydrolysis of these compounds m the gastio
intestinal tract compared with the rates in
parenteral depots can account for the ob-
served effects Another example concerns
3-phenyI-l,2,4-tnazole, which produces
strong centraJ nervous system stimulation
when mjected mtravenously and pronounced
depression when administered mtrapeii-
toncally
The examples ated so far demonstrate that
some drugs exhibit not only quantitative but
also quahtative differences m activity as a
function of route of admmistration These
differences may be due to differences in tis-
sue distnbution patterns, biotransformation
and physiologic availability from the gastro-
intestmal tract Relative drug stability m dii
ferent body compartments may also be in-
volved and will be discussed m a following
section Such effects must be considered m
any attempt to extrapolate pharmacologic
data oblamed after drug administration by
one route to mstanccs where the drug is ad-
ministered by another route This is obviously
pertinent to the mlelhgent mterpretation of
literature data and to rational development of
dosage forms
Blood Levels and Plasma
Protein Binding
Blood level data are widely employed to
evaluate the absorption rate of drugs as a
function of dosage form, route of adnunts-
tration and similar vanables This involves
no unusual complications m the majonty of
individual cases, smee the biologic properties
of a drug such as apparent volume of distri-
bution, elimination rate and activity are usu-
ally unchanged so that differences in blood
levels arc a direct reflection of differences m
absorption rate (Many of the possible com-
plicauons discussed in previous sections can
be avoided m a clinical evaluation by proper
experimental design ) The utilization of
blood levels as entena of the comparative
absorption efficacy and activity of a senes
of derivatives or homologs is not as simple,
and such data can easily be mismterpreted.
The vanous compounds, despite basic struc-
tural similarities, may differ cot^iderably m
activity, distribution pattern and biologic
half life, among other thmgs In such cases,
blood levels can be mteipreted rationally only
if the dissunilarities mentioned above are con-
sidered i»ncurrently Many drugs are bound
partially to plasma proteins and exist m the
blood m part as free drug and m part as drug-
protein complex. Only the free drug can
diffuse to other tissues, the protem-bound
portion does not pass across blood vessel
walls m the healthy individual The greater
the degree of protem bmding, the smaller the
amount of the drug which is available to
extravascular sites, smec the dnvmg force for
diffusion from blood stream to other tissues
IS the concentration gradient of diffusible
(not total) drug
Obviously, even an mherently active chemo-
therapeutic agent cannot be effective unless
It reaches Us site of action m sufficient con-
centration Some drugs are relatively meffec-
tive because they are highly protem bound,
while appropnately modified derivatives may
be quite active because of their lesser affinity
for plasma proteins The higher blood levels
obtamed after admmistiation of one com-
pound, as compared with the blood levels
resulung from administration of another de-
nvative, may mean either that the former is
more rapidly absorbed or that it is more ex-
tensively bound to plasma protems In the
latter case, the higher blood levels would be
indicative of low availability to extravascular
tissues and, probably, of low therapeutic
effectiveness
The generalities mentioned so far may be
discussed more specifically, usmg the sul-
fonamides and tetracyclines as examples
Both types of compounds are active only in
unbound (diffusible) form The binding of
sulfonamides to plasma proteins can be de-
senbedby the equation,
Dp=rKD? ( 16 )
where D, is the concentration of bound drug.
Of IS the concentration of free drug and K
and a are constants characteristic of a par-
ticular sulfonamide This equation is anal-
ogous to the Freundheh adsorption isotherm.
52 Dosoge Form Design and Evaluohon
Fig 21 Protein binding of various sul
fonanudcs in human blo^ scrum (from
Scholtan W Die Bmdung der Langzeit
Sulfonamide an die Eiwciss Korpcr des
Scrums Arzneun Forseh JJ 707)
which characterizes many adsorption proc-
esses It indicates that the degree of protem
binding is a function of concentration
This important point has been overlooked
by the many investigators who determined
the degree of protcm-biadiQg at only one
drug eoncentratioo Equation (16) is handled
more easily to logarithmic fonn
log Dp » log K + a log D, (17)
In this form, there exists a linear relationship
between log Dp and log Dt, with log K as the
intercept and a as the slope Such a log log
plot, representing the degree of protein bind
ing of a number of sulfonamides m human
scrum as a function of drug concentration,
IS shown in Figure 21 Several of the lines
intersect, which indicates that one drug may
6c more exleasiicly bound than another st
a low concentration, while the reverse is true
at higher concentrations In general, the dc
grcc of protein binding of any one sulfona
mide decreases with increasing drug concen
tration as cxcmplilied by the data shown m
Table 4 Only sulfadiazine and sulfamcrazmc
do not show this relationship, the micraction
of these compounds with plasma pnetcins is
practically independent of concentration The
iuifonamidc B 5254 is almost totally protem-
tiound at concentrations of 10 mg % or less
[t jiclds high blood levels but has no bac-
enostatic cltccl m vivo'*® because of its cx-
ircmcly low availability to cxlravascular
ircas The degree of plasma protein binding
Table 4 The Relation Between Free
Sulfonamide Concentration* and
Total Sulfonamide Concentration
IN Human Blood ScRUMf
Total Sulfonamide
Concentration
(mg %)
100
10
1
B5254t
44 0
004 <001
Sulfaphcnozole
31 0
0 63
001
Sulfadimethoxine
205
35
0 42
Sulfamethoxypyndazinc
45 0
13 5
21
Sulfamerazine
253
27 0
28 5
2 Sulfanilnmido 5
melbox) pyrimidine
55 0
31 0
127
Sulfadiazine
52 0
55 0
59 0
* Expressed as per ccot of total concentration
t Scholtan W Arioeun Forseh IJ 707
t S sulfanilamido-3-tibyI 1 2 4-thiadia2oIe
of sulfonamides differs considerably between
various animal species Moreover, the van-
ous species cannot be grouped m any distinct
order with respect to the relative magnitude
of plasma protem binding, a different se-
quence IS obtained with different sulfona-
mides Therefore, animal data have limited
value in assessments of the activity of sulfona-
mide drugs
When the degree of plasma protem bmd-
logof a drug decreases at higher blood Icvcb,
the apparent volume of distribution of the
drug wiH increase with increasing dose Ac-
cordingly, doubling an mtiavcnous dose may
not double the value obtamed by ex-
trapolating the drug concentration decay
curve to zero time (cf p 35) For ex-
ample, Do after intravenous administration
of if? Gm ot sodium saheyhte (mhich is
parliaiiy bound to plasma proteins) was 40
mg %, after intravenous admmistration of
20 Cm , Do increased to only about 55
mg % i»i As the relative intravascular re-
tention of such drugs decreases, a greater
fiaction reaches bioiransformaiion sites Tins
can result m higher biotransformation rates
and smaJJer half lives at higher doses, pro-
vided that there is no saturation of the con-
jugatmg system as previously desenbed Such
effects have been observed with lophcnoxic
acid* '** and phenylbutazone ^ It is of inter-
est that there is IittJe correlation between the
•Thu highly plaxma protein bound compound
cim bave a iulf life os I005 os yean in humacu’
Biologic Factors 53
degree of plasma-protein bmding and the ex-
cretion rate of sulfonamides Tbe kid-
neys evidently are capable of dissociatmg the
drug-protein complex Various pathologic
conditions cause changes in the composition
of plasma proteins and can affect the degree
of drug bmdmg Scholtaa'®* reports cases of
nephrosis, diabetes and cirrhosis where the
degree of plasma protein bmdmg of a sulfona-
mide was considerably lower than m healthy
subjects
Another mechanism by which the degree
of protem bmding of drugs can be reduced
and drug availabdity to extravascular areas
increased is displacement of the drug from
its adsorption site by another substance This
approach should be a most promising one for
enhancing drug action Amton found that
sulfinpyrazone, ethyl biscoumacetate, lophen
oxic acid and other substances displace sul*
fonamide from plasma protems, resulting in
a decrease of total drug plasma concentra-
tion and an increase of sulfonamide concen-
tration m the tissues ^
Effective displacmg agents are substances
highly bound to plasma protems, but certain
structural characteristics ace also required,
probably for adsorption site specificity Dis-
placement agents have not yet been tried m
chemotherapy as drug potentiating agents,
but unintentional displacement effects have
been observed clinically The protein bmding
of 2 sulfanilamido-5 mcthoxy pyrimidine was
very much decreased m a patient with high
serum biiirubm concentration due to curbosis
of the liver, bilirubm was found to displace
the sulfonamide from plasma protems also
m vitro On the other hand, there are in
dications that several fatal cases of keniio-
terns m premature babies were due to the
displacement of protem bound bilirubm by
sulfisoxazole, a sulfonamide which was used
prophylacUcally for its antibacterial effect
The freed bilirubm accumulated in the cen
tral nervous system of these infants and
reached toxic levels there It is likely
that m VIVO equilibrium between drugs or
physiologic substances and plasma proteins
is a funcUoa of concentration and respective
stability constants, precisely like the equilibna
of other types of reactions ITius, it is not
surpcismg ^at a sulfonamide can ihsplacc
protem bound biluaibm m one mstance, while
Table 5 Effect of Serum on Antibac-
terial Activity of Demethylchlor-
TETRACYCLINE AND TETRACYCLINE*
Minimal Inhibitory
Concentration
(meg /ml)
Demethyl-
chlortetra- Tetra-
CYCLINE
CYCLINE
Streptococcus — 9282
Broth
0 05
OOS
50% Serum
0 98
0 70
Streptococcus — CL 25
Broth
05
40
50% Serum
32 0
640
Staphylococcus — P
Brolh
01
02
50% Serum
08
08
Staphylococcus — T
Broth
0 05
02
50% Serum
32
16
Coh — Aerogenes— 1 19
Broth
05
I 0
50% Serum
40
20
• Roberts C E, et ol Demethyl chlortetracy
dine and tetracycline, Arch Intern Med 107 204
bilirubm replaces a sulfonamide m another
instance These clinical observations suggest
the potential usefulness of the displacement
method as a new and umque approach to
the potenUation of drugs it is likely that
further developments m this area will be
forthcoming
The use of blood level data to judge the
relative merits of antibiotics such as the
pemciilins and the tetracyclines is associated
with considerable difficulty and chance of
mismierpretation Both broth dilution and
agar diffusion assay methods tend to mini-
mize the effect of protem bmding and do not
reflect the concentration of diffusible drug
alone Smee different homologs may differ
considerably m their affinity to plasma pro-
teins, It IS not appropnatc to base judgment
solely on total drug levels m the blood This
IS exemplified by the data m Table 5, which
show that the greater in vitro activity of
dcmethyl-chlortetracycime as compared with
tetnu^clme (which is less protem bound) is
nullified and actually reversed m the presence
of serum Moreover, different tetracycline
homologs differ m their activity against a
given micro-orgamsm
54 Dosage Form Design and Evaluation
Fio 22 Scrum levels of 4
tetracyclines expressed in terms
of the administered homolog
{above) and in terms of tetra-
cycline activity {below) (From
Kunin, C Af , and Finland, M
Clinical pharmacology of the
tetrac>clinc antibiotics, Clin
Pharmacol iTherap 2 51)
CoflCcntrattOQs of vanous tctracydioes in
the blood, as determmed by nucrobiologic
assay, can be expressed either m terms of the
anubiotic ingested or m terms of tetrac^clmc
Itself The two methods yield dilTcrcnt results
and may show cither one or another tetra-
cycline denvative to be the most useful (sec
Hg 22) Since we arc interested m the ac-
tivity of such drugs against a particular
pathogen and not m their activity with re-
spect to the micro-organism used m the bio-
assay, it is apparent (hat this type of study
may not be scry helpful m the choice of the
most useful lelracyclme denvauve for Ucat-
mg a particular infection
In summary, it may be stated that blood
Joel data alone oiler an msuiUcient basis on
which to judge the relative merits of struc-
turally and pharmacologically related com-
pounds such as the sulfonamides, the peni-
cillins and the tetracyclines Differences m
plasma protem binding, antibacterial spec-
trum andpecuhantics of assay methods must
also be taxen mto account. Higli blood levels
may be indicauvc of low drug coacentratjon
m cxtravascular tissues and low chcmoihciv
apcutic cficcuvcness Pharmacists should
View the 'battle of blood levels" waged by
the sales promotion departments of some
pharmaceutical manufacturers with a good
deal of reservation and realize that there may
be a great deal more to the issue than that
which meets the eye
PHYSICAL and chemical FACTORS
Lipoid Solubility and Dissociatiov
Constant
The gastrointestinal epithelium acts as a
lipidlikc barrier to most drugs It permits die
absorption of lipoid soluble substances from
the gastromtcstmal tract by a process of pas-
sive diffusion, while lipoid insoluble sub-
stances can diffuse across this bamer only
with considerable difficulty, if at all Many
drugs arc cillicr weak, organic acids or bases
Depending on their dissociation constants
and on pH, they exist m soluuon partly
Physicol and Chemical Factors 55
ionized and partly m undissociated form
Only the undissociated form is lipoid-soluble,
and diffusion of drug across the gastrointesti-
nal membrane is restricted essentially to this
form Since the rate of diffusion is propor-
tional to the concentration gradient of dif-
fusible drug across the membrane, it is pos-
sible to increase the absorption rate of weak
acids and weak bases by appropnate pH ad-
justments As the pH is decreased, the con-
centration of the Undissociated form of a
weak acid mcreases and, therefore, the fate
of gastrointestinal absorption also is in-
creased
The same effect is obtained by mcreasmg
pH m the case of weak bases The expen-
mental data m support of these statements
have been summarized by Hogben®^ and by
Schanker
When the pH’s of fluids on opposite sides
of a membrane differ, it is possible for a
weak acid or base to concentrate on one side
Diffusion equilibrium mvolves only the un-
ionized portion of such substances, it wiU be
present on each side of the membrane in
equal concentration at equilibnum The con-
centration of total (dissociated and uodis-
sociated) drug will differ if the pH’s on the
opposite sides of the membrane are not the
same As an example, one may consider the
diffusion equilibrium of a weak acid (pK, =
4 0) between gastnc fluids (pH <=“ 1 ) and
blood (pH “7) Employing the Henderson-
Hasselbalch equation
pH — pK, + log
salt conc cntralion
acid concentratiOR
(18)
It may be calculated that at pH 7 the ratio
of undissociated to ionized drug is 1 1,000
while at pH 1 the ratio is I 0 001 Thus,
when the concentration of un ionized drug is
equal on both sides of the gastnc membrane,
the concentration ratio of total drug (gastnc
fluids blood) wUl be 1 001 1,001 or,
roughly, 1 1,000 These considerations pro-
vide explanations for the passive diffusion of
weakly acidic or basic drugs agamst what ap-
pears to be a concentration gradient (but is
not), and for the ‘ trapping” of such drugs in
certain fluids or tissues which differ m pH
from that of their environment.
Gastromtcslmal absorption of weakly
acidic or basic drugs is affected not only by
Table 6 Comparison Between Colonic
Absorption of Barbiturates in Rats
AND Chloroform Water Partition
Coefficient of the Undissociated
Drug*
BARBrrUBATE
pARimON
Coefficient
Percent
Absorbed
Barbital
07
12
Aprobarbital
49
17
Pbenobarbital
48
20
AUylbarbitunc acid
105
23
Bulethal
11 7
24
Cyclobarbital
13 9
24
Pentobarbital
28 0
30
Secobarbital
50 7
40
Hexelfaal
>100
44
* Scbanler, L S Absorption of drugs from
the rat colon, J Phannacol Exp Therap ]26 283
their degree of ionization but also by the
hpid solubility of their un-iomzed forms The
relative afBmty of a drug for lipids and for
water may be estunated on the basis of its
partition coefficient between a lipidhke sol-
vent and water The effect of partition co-
efficient 15 illustrated m Table 6, m whi^
are Jisted partition coefficients and degrees
of absoiption of a senes of barbiturates from
the colon of the rat The vatious barbiturates
have about the same dissociation constants,
so that differences m then gastrointestinal
absorption can be related directly to parti-
tion coefficients
The physicochemical factors of importance
m the gastromtestmal absorption of weakly
acidic or basic drugs suggest several methods
which may be used to mcrease absorption f
These involve either modifications m en-
vironmental pH or structural modifications
of the drug itself The pH of gastnc fluids
can be mcreased by administration of sodium
bicarbonate or other antacids This mcreases
the absorption of weak bases and decreases
the absorption of weak acids However, it is
important to consider also several other pos-
sible consequences of antacid administration
mcludmg modifications of urmary pH and
drug excretion rate, gastnc emptymg rate
and the dissolution rate of admmistercd drug
solids Changes m the pH of mtcstmal fluids
are diflicult to brmg about under clmical con-
t Compare Chapter 4 p 150 for specific apphea
uons.
56 Dosage Form Design and Evaluation
ditions Less diiCcuU are temporary pH modi-
fications at more accessible sites, such as the
c}c Basic buffer solutions have been cm-
plo)cd successfully to obtain increased phar-
macologic response from alkaloidal offfi-
thalmic solutions “
It IS often possible to make minor struc-
tural modiffcations in drugs (and thus to ob-
tain compounds w-ith greater lipid solubility
and more favorable dissociation constants)
without affcctmg significantly their intrm <iig
pharmacologic properties Such an approach
has resulted in the development of propionyl
erythromycin ester lauryl sulfate, a com-
pound which IS considerably better absorbed
than the weak base erythromycin itself The
pK, of erythromycin is 8 6, that of the ester
IS 6 9 Furthermore, the Iipid partition co-
efficient of the ester is about 180 times larger
than that of erythromycin * Another example
is the weak acid heparin, which is not ab-
sorbed at a pH above 4, esterification with
methanol yields a partially methylated com-
pound with unimpaired anticoagulant ac-
tivity, which is absorbed at pH s 5, 6 and 7 •-*
*nicse physicochemical considerations with
regard to the passage of drugs across the
gastrointestinal membrane arc aiso appli-
cable to other biologic banters, including
the one between blood and brain The
factors which favor drug penetration through
biologic membranes m general are a high
degree of Iipoid solubihty, a low degree of
ionization, and lack of plasma protein bind
mg
Dissolution Rate
Drugs which are administered oraUy m
solid form first must dissolve m gastro-
intestinal Quids before they can be absorbed
Dissolution takes time and frequently is the
rate limiting step m the absorption process
The dissolution of a substance m a non-
rcacung solvent may be described by the
Noycs-\Vhiincy law
= KS (C. - C) (19)
at
where dC/dt ts the rate of dissolution, S is
the surface area of the dissolving solid and
K IS the dissolution rate constant (which m-
cludcs several factors such as intensity of
agitation of the solvent and diffusion co-
c.niruMir of the dissolving drug). C is the
concentration of drug m the dissolution
medium at time t and C, is the concentration
of drug in the diffusion layer surrounding
the solid material This diffusion layer is a
thm film saturated with the drug, so that C,
IS essentially equivalent to the concentration
of a saturated solution The rate of dissolu-
tion IS governed by the rate of diffusion of
solute molecules through the diffusion layer
into the body of the solution
Equation (19) mdicates several ways by
which the dissolution rate of a drug may be
increased Smcc dissolution rate is directly
proportional to surface area, one may de-
crease particle size The greater surface area
of drug m contact with dissolution medium
then will bring about more rapid dissolution
and thereby more rapid gastromtcstmal ab-
sorption, provided that absorption is rate-
hmitcd by the dissolution process In m-
stances where the intrinsic dissolution rate
IS so low that the drug is ordinarily not com-
pletely absorbed when administered in solid
form, the more rapid absorption attained by
increasing the specific surface area will cause
also an increase in the total amount of drug
absorbed from a given dose
As an example, sulfadiazine, when given
as a fine particle suspension, is absorbed
more rapidly and more completely than when
administered as a suspension of larger par-
ticles The gastromtcstmal absorption rate
ofsulfacthylthiadiazolcalso is increased when
this drug IS administered m smaller particle
size**
One of the most stnkmg examples of the
role of dissolution rate and the effect of sur-
face area concerns the antifungal drug gnsco-
fulvm This substance is absorbed mcom-
plctcly because of its very low dissolution
rate, which is probably related to its poor
solubility m gastromtcstmal fluids It has
been found that the absorbability of gnsco-
fulvm mcrcascs Imeariy with the logarithm
of specific surface area, as shown m Figure
23 By Using 0 S Cm of finely micronized
drug It was possible to obtam the same blood
levels as those following administration of
I 0 Gm of the then available commcraal
form of the drug * As a result of such studies,
manufacturers now market gnscofulvm m
finely micronized or microcrystallme form,
which permits dosage reduction by 50 per
cent
physical and Chemical Factors 57
An interesting particle size effect has been,
observed m vetennaiy practice with respect
to the anthelmintic activity of phenothiazme
preparations The activity of these slowly
dissolving substances against parasites in the
small mtestine of lambs increases with lO-
creasmg surface area, as would be expected
from dissolution rate theory However, it
has been found that larger particles are
more effective against parasites mhabiUng
the large mtestine This is due apparently to
the smaller particles being dissolved and ab
sorbed before reaching the large mtestme,
while larger particles, because of their smaller
specific surface area, reach the large mtestme
and are able to exert an anthelmintic effect
there Obviously, this approach can also be
used m human chemotherapy where neces-
sary
The dissolution rate of drugs may also be
mcreased by mcreasmg their solubility m the
diffusion layer This would be reflected by an
mcrease m the value of the C« term m the
Noycs-Whitney equation In the case of
weakly acidic or basic drugs, C, can be m-
creased by modifying the pH of the diffusion
layer Considering a weak acid HA as an ex-
ample, Its total solubility Ci is the sum of
the concentrations of un ionized acid HA
and the anion A“
C,= [HA14-[A-] (20)
The total solubility of a ueak acid m aqueous
media at any pH usually is limited by the
solubility of Its un ionized form Smee
IH+] [A-I
[HA]
[HA]
IA-] = K.
IH+I
( 21 )
( 22 )
where K, is the dissociation constant of the
weak acid and the brackets refer to the con-
centrations of the indicated species m solu-
tion Substitution for [A~I m equation (20)
results m
C. = IHAI + K.f^ (23)
SVhentH+] <<K„
C. = K,
[HA]
[H+J
(24)
and, expressed m loganthnuc form,
log C. - log [HA] - pK, + pH (25)
From the last equation it can be seen that the
Fio 23 Effect of specific surface area
on absorbability of gnseofulvin (from
Atkinson, R M , er at Effect of particle
size on blood gnseofulvin levels m man,
Nature J93 588)
solubility Cl of a weak acid m the diffusion
layer mcreases with mcreasmg pH There
are several ways of mcreasmg pH of the
diffusion layer One may ( 1 ) increase the pH
of the entire dissolution medium as such, (2)
mix a basic substance such as sodium bi-
carbonate or sodium citrate with the weak
acid or (3) use a highly water soluble salt
of the weak acid instead of the weak acid
Itself
Using the first method listed and consider-
ing physiologic conditions, one may admm-
ister antacids and thereby raise the pH of
gastnc fluids m order to enhance the dissolu-
tion of weak acids The high acidity of the
gastnc fluids of course favors the dissolution
of weak bases and has an opposite effect on
weak acids The second abroach, that of
adding solid basic substances to a weak acid,
serves to mcrease pH m the immediate envi-
ronment of the weak acid solids This is the
basis of the so-called buffered aspinn tablets
and of combmations of other weak acids,
such as PAS, with calcium carbonate, mag-
nesium oxide and similar basic substances In
combmations such as these, there probably
exists an optimum ratio of the two compo-
nents which IS related, among other things,
to the strength of the weak acid and the de-
creasing fraction of total surface occupied
58 Dosage Form Design and Evotuoiion
Table 7 Effect of Dissolution Rate on Gastrointestinal Absorption and
Blood Sugar Lowering AcnviTy op Tolbutamide*
(Administered m Pure Form as Nondismtcgratmg Pellets)
Form op
In Vitro Dissolution RATEt
Amount of Drug
Lowering of
Blood Sugar
Tolbutamide
0 1 N HCl
pH 7 2 Buffer
IN BODYt
Level§
Acid
21
31
14
52
Sodium salt
1069
868
251
19 1
* Nelson, £., ft ol loUueoce of tlie absomion rate of lolbutanude oa the rale of decline of blood
sugar levels m oonnal humans, f Pbann Sa St 509
tlniDg of tolbutanude (acid forml/cmVhir
t In mg of tolbutamide (acid form) I hour after oral ingestion of 500 mg of tolbutamide (or equiva
lent) , average of four subjects,
f In mg per cent, I hour after drug administration
by It as the proportion of addiQvc la the
mixture is mereased
The most effective means of atta ining
higher dissolution rates is to use a highly
watcT'Solublc salt of the \tcak acid instead
of the free acid itself The salt acts as its own
buffer and markedly raises the pH of an
acidic dissolution medium in the immediate
environment surroundiog the dissolving drug
solids The dissolution rate of the sodium salt
of a weik acid m an acidic dissolution medium
under certain circumsianccs may be 1,000-
fold higher than the dissolution rate of the
weak acid itself Even if the sodium salt
picopita^ subsequently as the free acid tn
the bulk phase of an acidic solution such as
gastric Quid, it will do so usually tn the form
of Very fine particles The large surface area
of the drug thus precipitated favors rapid
dissolution as additional fluid becomes avail'
able or as some of the dissolved drug is re-
moved by absorption The wtnnsicalJy more
rapid dissolution of salts of most weak acids
as compared with that of weak acids them-
selves may be overshadowed, of course, by
other factors, such as differences in particle
size and tn the physical properties of their
dosage forms
The dosage form and the surface area
factors have been kepi essentially constant m
a comparative study of the absorption and re-
sultant blood sugar lowering activity of the
weak acid tolbutamide and sevend of its
salts This was accomplished by the use
of nondismtcgratmg pellets conlammg only
the respccuvc drug and no additives In this
way it was possible to establish the effect of
dissolution rate on the absorption rate and
the pharmacologic activity of the drug Part
of the results of this study are summarized
m Table 7 The greater activity of the sodium
salt as compared with the acid form of
lolbmamide is readily apparent
Differences m m-vivo dissolution rale be-
tween weak acids and their water-soluble salts
are greatest at low pH and often dimmish at
higher pH Thus, such differences would
show up most prominently m gastnc fluids
This IS well illustrated by the findings of Lee
c/uf who have studied the absorption of
peruciJlin V when adnumstcred as the free
acid and as the sodium salt, respectively,
from the stomach and the small mtesunc of
the dog The results, depicted in Figures
24 and 25, show that drug absorption from
the stomach was much more rapid after ad-
mimstratioo of the sodium salt but that there
was essentially no difference when the two
forms were mtroduced directly into the
duodenum Ihc role of gastnc motility m
clinical evaluations becomes apparent here,
prolonged retention of the drugs m the stom-
ach w dl accentuate the differences m absorp-
tion rate, while clmical exjadtUoas which
favor rapid stomach emptying will rend to
dimmish the differences between the two
forms
Cottclauon between mtnnsic dissolution
rate and gastromtcsUnal absorption has been
demonstrated also m model expenmeots
usmg Ictracjclmc and some of its salts’*®
These studies also have shown that the
absorption rate of the slowly-dissolvmg iclra-
Qchne was mcrcascd by usmg drug bavmg
a greater specific surface area (smaller par-
ticles) However, this effect was not noted
Physical and Chemical Factors 59
Fig 24 Serum levels of penicillin V lo
dogs, resulting from gastnc absorption of
drug administered as the free acid and the
potassium salt, respectively, to animals
whose stomachs were sectioned from the
duodenum (From Lee C C ,et al Gas
tnc and intestinal absorption of potassium
penicillin V and the free acid Antibiot &
Chcmotber 5 354)
with the much more rapidly dissolvmg tetra-
cycline hydrochloride, thus indicating that
(^solution rate was no longer the rate-deter-
nuning factor in gastrointestinal absorption
when tetracycline was administered as the
hydroclilonde The observations with tetra-
cycline hydrochloride should be expected,
smce this drug is absorbed mainly from the
intestine and only slightly from the stom-
ach Unless dissolution is extremely slow,
the rate of transfer of the drug from stomach
to mtestme, rather than the dissolution rate,
would be rate limiting m the absorption
process
In coosidermg the importance of specific
surface area with respect to dissolution rate,
one must distinguish between surface area as
detenmned by standard methods such as
mtrogen adsorption and what will be desig-
nated here as effective surface area The
latter term refers to the area which is m actual
contact with solvent and which is subjected
to the agitation conditions pievaiUng in the
dissolution medium The difference in mcan-
mg between the two terms will become ap-
parent on descnption of the following ex-
periment Wurster and Seitz have prepared
cylindncal pellets and have drilled several
pores of about 1 ram diameter into some
these Although the surface area of the
Fro 25 Serum levels of penicillin V m
fistular dogs after intraduodenal admims-
ttmion of free acid and pousswim salt,
respectively (From Lee, C. C , el a!
Antibiot & Cbemother 8 354)
pellets was thereby mercased 20 per cent,
dissolution rate increased by only 4 per cent
as compared with the pellets without pores
Gearly, the surface m the pores was not fully
available to the solvent Also, the mtensity
of ablation could not be the same in the
pores as at the external surface of the pellets
The limited availability of the pore surface
was due, m part at least, to occlusion by air
Better penetration of solvent was obtained
when Its surface tension was lowered by addi-
tion of sodium lauryl sulfate The surface
of the granules liberated by the disintegration
of tablets and the surface of other aggregates
of drug solids are also somewhat irregular,
presenting crevices and pores to the dissolu-
tion medium It will be explained m the sec-
tion devoted to pharmaceutical formulation
factors that the approach described on p 58
may be used to increase the dissolution
rate of drugs contained m such forms
Another rather mterestmg surface effect
has been observed recently This mvolves the
deposition of a water msoluble film on the
surface from which dissolution is tabng
place When alummum aspirin was dis-
solved m a medium of pH 8 under conditions
which were such that dissolution should take
place at a constant rate (negligible drug con-
centration m the dissolution medium and con-
stant surface area), it was found that the
rate o' dissolution actually decreased with
tune This did not occur with plain aspitm
or when the aluminum complexing agent
60 Dosage Form Design ond Evaluation
Fw 7& o{ aspava aad
aluminum aspirm m 0 1 M Tns buffer of
pH 80 (A) aspino (•} aluminum as*
pirm (O) aluminum asptnn with l*^o
tOTA added to dissolution medium
Amounts arc expressed m terms of mg of
salicylic acid (From Levy, G . and Prock
nail J A Unusual dissolution behavior
due to film formation, J Pharm Sci SI
294)
cthylcncdiammc tctraacetic acid was added
to the medium (Fig 26) It was estabbshed
that, at basic pH, a wa(cr>msoIubfe basic
aluminum compound was formed and dc*
posited on the solid surface, thus retarding
further dissolution Similar effects evidently
occur m the intestine, because the absorp*
tion of aspirin from aluminum aspino seems
to dimmish considerably once the drug leaves
the stomach and enters the intestine
Salts of a base and a poorly soluble acid may
exhibit similar effects upon dissolution m
acidic media, where a film of the acid may
deposit on the drug surface
This discussion of dissolution rates and
their biopharmaceutical importance cannot
be concluded without making the simple but
critical distinction between solubibty and
dissolution rate The former refers to on
cquihbnum condition while the latter in*
volvcs a kinetic situation High solubility is
not necessarily associated with high dissolu*
tion rate, although solubility is one of the
several factors affecting dissolution rate
Saturation is rarely reached m gastrointestinal
and other biologic fluids smcc absorption, dis-
tribution and other processes constantly re-
move dissolved drug The important factor
IS how rapidly solid drug dissolves and thus
converts into absorbable and diffusible form,
because dissolution rate, rather than satura-
tion of biologic Quids with respect to the drug,
IS usually the absorption or diffusion limiting
factor
Crystal Form
Many drugs can exist in two or more
crystallmc forms with different space httice
arrangements This property is known as
polymorphism The various polymorphic
forms usually axhibit different x ray diffrac-
tion patterns, infrared spectra, densities,
melting points and solubilities As a result
ot different solubilities, the polymorphic
forms may also differ with respect to tlicir
intrinsic dissolution rates * For this reason,
one polymorph may be more effective m
chemotherapy tlian another polymorphic
form of the same drug
Many drugs may be prepared m a par-
ticular polymorpluc form by appropriate
choice of ciystaUization conditions (solvent,
temperature and crystallization rate), by
melting and subsequent cooling at particular
rates, by use of pressure or by the intentional
addition of impurities Only one form of the
pure drug is stable at a given temperature and
pressure (other than the transition point)
The other forms will convert in time to the
stable one This transformation may be quite
rapid or very slow A polymorph which,
though thermodynamically unstable, trans-
forms only slowly to the stable form, is re-
ferred to as mctastabic Many mctastabic
polymorphs can be considered stable in terms
of pharmaceutical use, on the basis of the
usual shelf life of pharmaceutical products
The stable polymorph usually has the highest
melting point, the greatest chemical stability
and the lowest solubility Mctastabic forms
arc sometimes preferred in pharmaceutical
preparations m view of their higher solubil-
ities and dissolution rates For example,
riboflavin can exist in three different poly-
morphic forms, having a solubility in water
at 25* of 60 mg , 80 mg , and 1,200 mg per
* It has been stated previously that dissoIuUon
rate is not necessanly proportioDo] lo solubility,
since other factors are involved m the dissolubon
process. However, m the case of several ph)ticai
modifications of one and the tame drug, dissolu
Uon rale ordinarily increases with solubility
Physical and Chernical Factors 61
liter, respectively ** It is evident that the most
soluble form of this vitamin can be particu-
larly useful m certam pharmaceutical prod-
ucts, such as powdered parenteral formu-
lations that are constituted before use by
addition of water
The rate of absorption of drugs admuus-
tered m solid form may be increased by use
of the most rapidly dissolving polymorph
In the case of meAyl prednisolone, which
was admmistered to rats by subcutaneous im-
plantation, It could be shown that the mean
absorption rate from the more soluble poly-
morphic form II was about 1 7 limes as
high as that from the stable and less soluble
polymorph I This difference reflects the
difference in dissolution rate between the two
forms
Though pnmaxily of toxicologic mtcrcst,
it may be pointed out that the various poly-
morphic forms of sihca differ m their tend-
ency to cause silicosis, a condition involv-
ing the formation and progressive growth of
collagenous nodules m the lungs due to in-
halation of finely powdered sdicas How-
ever, there seems to be no correlation be-
tween fibrogenic effect and dissolution rate
Rather, the toxic effect appears to be related
to crystal structure as such
The different polymorphic forms of a drug
exhibit difference m their properties only m
the solid state It is believed that, once m
solution, the polymoiphs lose their identity
and become indistinguishable from one an-
other However, there are recent reports from
Russian workers that different polymorphic
forms of certam orgamc acids may exhibit
different dissociation constants m solu-
tion The differences are more pro-
nounced at higher coocentrations of solute
and m solvents of low polanty These ob-
servaUons refer perhaps to nonequilibnum
conditions, and their biopharmaceutical
significance is yet to be assessed The re-
ported differences m dissociation constants
may mean that different polymorphs can have
different oil.water partition coefficients, a
possibility that has already been suggested ”
This may have pertinence to the formulatioa
of parenteral products containing an od as
the vehicle
In view of the possible effect of crystal
form on absorpuon rate and thereby on phar-
macologic activity, it IS necessary to consider
this proper^ as an additional variable m
pharmaceutical formulation and evaluation
It has been estimated that at least one third
of all organic compounds are polymorphic.*®
About one half of 22 barbituric acid de-
rivatives and 11 of 16 sex hormones were
found to have polymorphic forms Some of
these drugs have as many as four or five poly-
morphic modifications"® Cortisone acetate
occurs in at least five distinct ciystallme
forms, and an examination of 4 brands of
cortisone acetate tablets has revealed that
2 contained Form I and the others Form II
of the dmg®*^ Future revisions of official
compendia may be expected to incorporate
standards that will distinguish between poly-
morphs m cases where the various forms
may exhibit significantly different pharma-
cologic activities due to differences m dissolu-
tion rate and other physical properties,
Smee metastable modifications of a drug
ate often absorbed more rapidly, it becomes
desirable to determine rates of transfonnation
to the stable form and to find means of re-
tarding this transformation An example of
such a rate study is that by Tamura and
Kuwano,’*® who determmed the transition
velocity of chloramphenicol palmitate from
the amorphous and the o-forms to the
form- A number of polymorphic transforma-
tion studies With nondrugs are described by
Van Hook m a recent book^*® to which the
mterested reader may refer An otherwise
unstable polymorphic form may be stabilized
by tbe iniention^ inclusion of impuriucs
This IS possible when the dunensions of the
atoms of tbe impunty are such that they can
fit only mto a particular lattice arrangement
of the polymorphic compound Rearrange-
ment of the lattice into another, perhaps
mom stable, polymorphic form may then be-
come impossible because the \oids m the
stable lattice arrangement carmot contam the
irapunly without fine lattice being subjected
to very high stress Polymorphic transforma-
tion m suspensions may also be retarded by
increasing the viscosity of the medium or by
addition of substances that are capable of
adsotbmg on the crystals
From the point of view of physical and
chemical stability, it is often advantageous to
use a drug m its thermodynamically most
62 Dosoge Form Design and Evatuation
stable pol)morphic form The latter is
usually most resistant to chemical degrada-
tion, and this advantage is mcreased further
in the case of suspensions by the loucr solu-
bility of the stable polymorph.^ In addition,
the conversion of one polymorphic form to
another in suspensions may be accompamed
by caking and, in the case of parenteral sus-
pensions, by poor syringcabihty Thus, the
greater physical and chemical stability of one
polymorph may have to be weighed against
the greater physiologic availabihty of another
form
There are factors other than polymorphism
which can account for differences m phystco*
chemical properties of drug solids Such
factors include modifications of crystal habit,
formation of hydrates or other solvates and
the property of a drug to exist in either
crystallme or amorphous form The growth
rate of a crystal may be modified by certain
additives and by pH An addiuvc may retard
the growth of the several faces of a crystal to
di^erent extents, thereby causing modifica-
tions of crystal habit In this manner, one
may obtain a drug in the form of either fine
needles or thin plates, for example Smcc the
rates of dissolution from the various faces
may differ, it is possible to modify over-
all dissolution rates by crystal habit changes
which arc accompanied by changes in sur-
face area ratios between the various crystal
faces
A significant number of organic mcdicmals
can form solvent addition compounds or
solvates Quinine, sulfonamides, steroids,
barbiturates, xanthines and telracyclmcs can
fonsv hydsate sicucluccs These can dittex
markedly from their anhydrous equivalents
with respect to dissolution rate Ihc anhy-
drous forms of caffemc, thcophyllme and
glutcthimide have higher dissolution rates
than their respective hydrates, while organic
solvates (n omylate and ethyl acetate) of
fludrocortisone acetate dissolve much more
rapidly than the nonsolvatcd form of the
drug This presents another method for
modifying dissolution rales of pharma-
ceuticals
Finally, it is of importance to consider the
case m which a dnig can exist m other
crystallme or amorphous form The amor-
phous form is always more soluble than the
Mrresponding crystallme form“ and, there-
fore, may exhibit quantitatively different
pharmacologic properties The antibiotic
novobiocin, for example, is not absorbed to
any significant extent when adnunistcrcd m
crystallme fonn and, thus, is therapeutically
inactive However, the amorphous drug is
absorbed readily and is therapeutically cffcc-
livc Amorphous novobiocin is at least ten
tunes more soluble initially than the crystal-
line drug and exhibits similar differences m
dissolution rate Although amorphous novo-
biocm lends to ciystallizc m suspension, it is
possible to retard this transformation con-
siderably by addition of mclhylceUulosc One
may thereby prepare a suspension dosage
form of adequate stability and therapeutic
efficacy
One of the most striking and potentially
most cniical differences in therapeutic ac-
tivity between crystalline and amorphous
drug pertains to chloramphenicol, an anti-
biotic which IS usually reserved for the treat-
ment of senous and potentially life-threat-
coing infections It has been found that the
crystallme forms of chloramphenicol stearate
and chloramphenicol palmitatc arc thera-
peutically inactive and that only the amor-
hous forms of these two compounds are
ydrolyzed m the gastromtcsunal tract to
yield absorbable chloramphenicol * The spec-
ifications for chloramphenicol palmitate m
the US P XVI do not distinguish between
biologically active and inactive forms, and
one must rely on the conscieniiousncss and
vigilance of the manufacturer to assure the
of this impoctawt, drug
Drug Stability in Gastrointestinal
Fluids
Drugs must remain sufficiently stable cot
only during stomge (subject to appropriate
storage condiiioas and limitations of sbclf-
Itfe) but also m gostromlcstinol fluids Any
chemical change due to pH or cozy me action
and resulting ui a product that is pharma-
cologically inactive or less active than the
administered substance sliould be prevented
or minimized This may be accomplished
sometimes by chemical modification of the
parent molecule to )icld new dcnvaiivcs
Physical and Chemical Factors
63
Tlus approach is exemplified by the greater
efficacy of orally administered penicillm V as
compared with orally administered penicillin
G, due to the greater acid stability of the
fonner Enteric coatings, if properly formu-
lated, can prevent exposure of a drug to
gastric pH and enzymes and mipimi^g deg-
radation due to one of these factors The
oral mefficacy of drugs because of acid hy-
drolysis m gastnc fluids generally should
be predictable by fonnal kmetic studies, as
was done with p-chlorobenzaldoxime ** This
muscle relaxant, though active parentcrally,
is meffective when administered orally It has
a stability half life of less than 20 minutes
m the stomach and thus is largely hydrolized
to the aldehyde before bemg absorbed ** The
low potency of orally adnumstered nilro-
glyccnn and erylhrol tetraiutrate is also be-
lieved to be due to the mstabiUty of these
drugs m the gastromtestmal tract Some
compounds, though unstable m acidic solu-
tion, are protected from the destructive effect
of gastnc fluids by their hydrophobic surface
Such compounds are poorly wetted by aque-
ous fluids, and chemical mteraction is de-
creased by the restricted contact. Esters of
chloramphenicol and erythromycin exhibit
this property" In the case of chlor
ampbemcol esters, hydrolysis m the intestine,
being a prerequisite for absorption of the
parent drug, can be promoted by use of sur-
factants and by administering the drug m
finely divided fonn Erythromycin and its
esters are inactivated by g^tnc fluids, and
low wettability is m this case a desirable
protective feature Stephens and co-workers
have shown that although propionyl erythro-
mycin yields satisfactoiy blood levels when
administered m capsule form, addition of a
wettmg agent (5% polyoxyethylene sorbitan
mono-oleate) to the contents of the capsule
results m much lower blood levels, evidently
due to greater degradation of the drug in gas-
tric fluids
Degradation of slowly dissolving drugs in
gastric fluids can also ^ muimuzed by ad-
mimstenog such drup m the form of rela-
tively large particles Dissolution rate is
thereby reduced, less of the drug dissolves m
the stomach and less is therefore destroyed
by gastnc fluids However, if the particles arc
Fig 27 Relatiousbip between area be-
neath cryihromyciD blood level curves and
dissolution rate of vonous forms of erytb
romycin in 0 1 N HCI Erythromyem
(E.) propionate, 1, E acetate, 2, E acry-
late, 3, E isobutyrate, 4, E, n butyrate, 5,
free £., 6 (From Nelson, E Physico-
chemical factors influencing the absorp-
tion of eiythromycin and its esters, Chem
Phaim. Bull , JO 1099)
too large, they may dissolve so slowly that
they arc not fully biologically available Op-
timum particle size, therefore, is in some in-
termediate range where dissolution is slow
enough to prevent extensive degradauon of
drag m the stomach and yet sufficiently rapid
to assure complete dissolution before the
drug passes absorption sites This balance of
relatively low dissolution rate m acidic fluids
(to minunize degradation m the stomach)
and relatively hi^ dissolution rate in sbghtly
basic media (to assure rapid and complete
absorption in the mtestine) sometimes may
be achieved by appropriate chemical modi-
fication Nelson has shown this elegantly for
erythromyem and several of its esters He
Im demonstrated an inverse relationship be-
tween the dissolution rate of the eryihro-
mjem compounds in 0 I N hjdrochlonc acid
and the amount absorbed from the gastro-
mtcstmal tract (Fig 27), and a direct rela-
tionship between dissolution rate at pH 7 4
and amount desorbed (Fig 23)
64 Dosage Form Design and Evoluolion
Z 4 6 a 10 It
RATE mg/cm^/min X to*
Fio 28 Rclatioaship between area be*
ncalh erythromycin blood level curves and
dissolution rate of various forms of eryth-
romycin in 0 1 M borate buffer of pH 7 4
Numbers designate various compounds as
listed under Figure 27 (From Nelson, E
Physicochemical factors mduencing the
absorption of erythromycin and us esten,
Chem Pharm DuU , 10 1099)
COMPLEXATION
Drugs may interact reversibly to form com-
plexes With substances occurring in the body,
with other drugs and with pharmacologically
inert components of pharmaceutical dosage
forms The stability of these complexes under
defined conditions can be described by a sta-
bility constant Ko. uhere
_ {Drug — Complex]
” ” (Free Drue] [Free Complcxing Agenij
(26)
Equation (26) refers to a 1 1 complex, the
bracketed terms indicate molar concentra-
tions Equilibna mvolvmg complexes of dif-
ferent stoichiometry can be described by simi-
lar expressions Equation (26) is based on
the equilibrium
Drug + Complexing Agent Drug — Complex
(27)
The drug complex differs from the free drug
with respect to solubility, diffusivity, partition
coefficient and other properties More impor-
tant, drug contained in a complex is usually
pharmacologically mefTectivc The complex
ordmarily must dissociate at some stage m
the body before the drug can exert its usuaf
pharmacologic effect
The drug complex will usually differ from
the free drug itself with respect to its ability
to penetrate biologic membranes This may
be due to differences m physicochemic^
properties between the two forms, or because
the molecules of complexing agent are so
large that they cannot pass through biologic
membranes
It IS important to distinguish between the
equilibrium and the kinetic aspects of drug
complexes This may be done by coosiderug
the mteracuon of a drug with a macromolecu*
lar substance, resulting in a drug complex
which, due to its large size, cannot penetrate
biologic membranes or artificial membranes
with fine pores (such as dialysis membranes).
If one places an aqueous solution of both
drug and complexing agent into a dialysis
ba^ immerses the latter in a beaker of w-ater
and permits the system to come to equilib-
num, the species distnbute m a manner
shown in the diagram below The double
arrows across the membrane mdicate that
Membrane
[Drug Complex] ‘ r'. IDnigl , * [Drug]
1 1
t Macromolecular *]
Complexing Agent J
Inside Solution
Outside Solution
Physical and Chemical Foctors 65
£ree drug is diffusible and that it exists m
essentially equal concentration on both sides
of the membrane The drug complex and the
complexmg agent cannot pass through the
mei^rane and renum inside the dialysis bag.
If the drug in the outside solution is con-*
stantly removed by some mechamsm, the
situation may be depicted by the diagram
below Here there exists a nonequihbnum
condition, where the drug complex eventually
dissociates completely and all of the drug
passes across the membrane In the equilib-
rium case, only part of the ordinarily avail-
able drug IS available to the environment out-
side the membrane In the nonequilibnum
case, all of the drug is available but not as
rapidly as it would be in the absence of com-
plexmg agent. This follows from the fact that
the rate of diffusion from the inside solution
IS a function of the concentration gradient of
diffustble drug across the membrane and
not of total drug The problem of drug bind-
mg by plasma proteins (which has been dis-
cussed m a previous section) is represented
essentially by the nonequilibnum mode! de-
senbed here Suitably modified to account
foe penetcdile complexes which differ from
the free drug with respect to rate of mem-
brane penetration and considenog possible
competition by other substances for both
drug and complexiog agent, the model can
represent the conditions which may be found
m the body.
Drug complexation with nonabsorbable
macromolecules can be a useful method of
retarding drug absorption and thereby tc-
duemg toxiaty Polyvinylpyrrolidone can re-
duce the oral toucity of iodine, rucohne,
potassium cyamde and other drugs m this
manner * Where the free drug is a local im-
tant, complexation may prevent or reduce
imtation by keeping the concentration of
ffM drug low This approach has been used
to rechice the skm imtation liability of
iodine** and the gastrointestmal and tissue
imtation caused by iron compounds “ On
the other hand, nomntended complexation of
a dnig with other components of its phanna-
ceutical dosage form may reduce the effec-
tiveness of the preparation due to the slower
absorption of the drug Many suspending,
emulsifying and solubih^g agents form com-
plexes with certam drugs, but, fortunately,
most of these complexes are not very strong
and dissociate readily on dilution of foe prep-
aration m the gastrointestmal tract The prob-
lem is more acute m ammal experiments,
where comparative dosages and actual con-
centrauons may be much higher than m ordi-
nary human chemotherapy This is particu-
larly pertinent m animal toxicity studies and
m the mterpretauon of certam other phar-
macologic data obtained from ammal ex-
penmenis For example, it has been stated
foal solubilizers have occasionally mteifered
with the biologic activity of nboflavm
Complexauon often serves as a means of
increasing foe solubility of a drug Compared
with a suspension, a solution contammg drug,
a portion of which is complexed, may be more
effective (or more toxic) because dissociation
of foe complex can occur almost instantane-
ously on dilution, whereas dissolution of sus-
pended drug solids occurs at much lower
rates This aspect has been discussed m
gtcalcr detail by Werner with respect to LD50
dctennmations mrals
Some drug complexes penetrate biologic
barriers more readily than foe free drug itself.
(Drug CoroplexJ
^IDnigJ-
{
Macromolecula/
Complexmg AgePt
]
Membrane
CDnigl
Inside Solution
Outside Solution
66 Dosoge Form Design ond Evaluation
This may be a means of obtaining mcreased
drug activity, provided that the drug is re-
leased from the complex at or prior to reach-
ing Its site of action The gastromtesUnal
absorption of iron has been mensased by
complexation with citrate, p)Tophosphatc and
EDTA, but the amount of iron actually re-
maining m the body was less than when the
drug was administered alone, because the
complexes did not dissociate significantly and
also were excreted much more rapidly than
iron itself The degree of dissociation of a
metal complex m the body depends to some
extent on the concentration of the metal m
body fluids Animals defiacnt m calcium arc
more capable of taking calcium from the
complex than normal, “calcium saturated ’
anunals The same appears to apply to
iron This follows from considerations of
the physical-chemical equilibrium involved
Complexation may also reduce the ab-
sorbabuity of a drug coosidcrably, as in the
case of the tciracyclmcs The complexes
formed by these drugs with divalent and tri-
valent cations are absorbed much less efli-
cicntly than are uncomplexed tetracycimes
The binding of (etrac)clincs by protein
macfomoicculcs appears to be mediated by
the metal ions, which apparently serve as a
connecting bndge bctv>ccn the drug and the
protein molccidcs ” Such an interaction
could be the one responsible for the poor
absorption of tetracycline complexes from the
gastrointestinal tract
Calcium apparently pl3)s an important
role in the normal phjsiolo^ of gasuomtcslj-
nal membranes The chelating agent sodium
cthyicncdiammc tetraacetate (EDTA) causes
mucosal cells to become detached from the
rcmainmg tissue due to removal of calcium
The permeability of the membrane to pas-
sively diffusing substances is increased in the
presence of EDTA, perhaps because the
‘pores’ in Uic membrane arc increased or
spaces between epithelial cells arc widened
inrough removal of calcium Thus, the ab-
sorption of several neutral, acidic and basic
lipid insoluble organic compounds from the
gastromtesUnal tract is increased by EDTA
'^cse substances, which include mamutol,
mulin, a quaternary ammoruum compound
and sulfaniUc acid, arc very poorly absorbed
undcrordinarycircumstanccs Hepann, which
normally is not absorbed at all from the
gastromtcstinol tract, is absorbed m the
presence of EDTA In some instances,
however, EDTA and otlicr calcium binding
substances may reduce gastromtesUnal atv
sorpuon Evidently this involv es more compli-
cated mechanisms, such as reduced utilizaUon
of glucose and mhibiUon of tronsmucosal
transport of glucose and water These factors
m turn may inhibit the absorption of certam
dru^, mcluding barbiturates, strychmne and
sulfonamides * ^ *'* The use of EDTA to
obtain the effects described m these para-
graphs is thus rcsUictcd to investigational
purposes It is unlikely that this agent will
be used m chemotherapy to achieve simi-
lar results, m view of the deleterious effects
of rcmovmg esscnual trace metals from the
body However, the experiments referred to
ace useful for obtaining a better undeistand-
tog of the effects to be anUcipated following
the administration of drugs or additives which
are effective complexing agents Such effects
would be most nouccable m instances where
the drug is not significantly diluted by body
fluids m the course of admmistrauon, as, for
example, on application to the cornea, or by
the rectal route For additional discussion of
the pharmaceutical and phannacologic as-
pects of complexation, the reader may refer
to review articles by Marcus*** and by
Wemer *®*
Surface-Active Agents
Surface-active agents (surfactants) arc
used so widely as emulsifiers, solubilizers and
foimulatjoa adjuncts tliat their effect on drug
absorption requires careful consideration
Smcc these substances can affect the mtcgrity
of biologic membranes, it has been thought
that they might be effective absorption-
enhancing agents However, reports concern-
mg the usefulness of surfacc-aciivc agents m
CD^anang the gastrointestinal absorption of
drugs have been conflicting Enhancement as
well as inhibiUon of the gastrointestinal ab-
sorption and the pharmacologic acuvity of
drugs has been observed when surface-active
agents were added to a medication Many of
these reports have been reviewed and sum-
marized by Blanpin ** Much of tlic difficulty
with some of tlic studies probably has been
due to the different t)pcs of effects which
Physical and Chemical Factors
67
surface-active agents can exert Briefly, fliqr
may act on the biologic membrane, the drug
or the dosage form as such Some suifece-
acUve agents also have pharmacologic prop-
erties specific to their particular chemical
structure and not related to their surfactant
property m general Several of the listed
effects may be operative at the same tune,
the magmtude of each bemg dependent on
concentration to a different degree Tins com-
plexity can make proper assessment of sur-
factant effects very difficult and indicates the
need for careful expenmental design of studies
concerned with the biopharmaceuttcal and
pharmacologic effects of surface-active agents
The two major mechamsms of surfaaant
activity with respect to drug absorption are
described comprehensively m a senes of re-
ports dealmg with the kinetics of rectal ab-
sorption The rate of absorption of sodium
iodide was found to be accelerated 4 to 5
times by small amounts of polysorbate 20 and
sodium lauryl sulfate, while the rate of ab-
sorption of iodoform and tniodopheool was
retarded by the same agents The accelerated
absorption of sodium iodide was attributed
to the surface tension lowering and mucous
peptizing action of the surface-active agents,
which results in greater contact of drug with
the absorbing membrane On the other band,
the retarding effect in the case of iodoform
and truodophenol evidently is due to the en-
trapment of these drugs in surfactant micelles
(Sodium iodide is not affected lo this man-
ner } This type of uiteiaclion is a special
case of compicxation, as descnbed in the
previous subsection Aggregates of surface-
active agent molecules (micelles) arc too
large to pass through biologic membranes,
and drug molecules bound in these nucelles
cannot be absorbed The low absorption rate
of iodoform and truodophenol m the pres-
ence of surface active agents is a reflection
of the lowered concentration gradient of dif-
fusible drug across the membranes Micelle
formauon docs not take place until the con-
centration of surface active agent exceeds a
certam value known os the cntical micelle
concentration (CMC) Surfactants can thus
exert a two-phase effect which is a function
of concentraiion Below the CMC, absorp-
tion of drugs may be enhanced due to better
contact of drug soluuon with the membrane.
this IS a “wetting" or spreadmg effect result-
mg from a decrease m the surface tension of
the solution
Above the CMC, a portion of the drug
molecules may become entrapped m micelles
and, as such, be unavailable for absorption
The wettmg as well as a peptizmg effect is
also operative, and the net effect (absorption
enhancement or retardation) depends to
some degree on the relative magmtude of
mteraction between drug and surfactant The
absorption-retardmg effect usually predom-
mates at higher surfactant concentrations be-
cause a larger fraction of the drug is bound to
micelles However, repeated or prolonged
exposure to high doses of a surface-active
agent may lead to partial disruption of bio-
logic membranes and thereby reduce their
barrier effect significantly
The concentration-dependent activity of
surfactants is well illustrated by their effect
on the bactericidal activity of phenols The
effectiveness of the phenols is mcreased with
increasing surfactant concentration until the
CMC IS reached At this pomt the bactencidal
activity IS at Its maximum As additional sur«
factant is added, the activity of the phenols
1 $ successively reduced until they become
practically inactivated Is more complex
environmcnu such as the gastromtestmal
tract, one must also consider ffie competition
by certam physiologic substances with the
drug molecules for micellular bmdmg sites
Thus, It is evident that the nature and the
magnitude of the effect exerted by surface-
active agents can be highly dependent on
concentration It should not be considered
unusual for different groups of mvestigators
to attribute absorption enhancing and ab-
sorption retarding activity, respectively, to a
particular surface-active agent, even with re-
spect to the same drug, since the different
workers could have empbyed different con-
centrations of surfactant or different experi-
mental procedures
Aniomc surfactants can form msoluble
precipitates with large drug cations, and
cationic surfactants can mtcract similarly
with large drug anions The insoluble com-
pounds thus formed are often not absorbable
and combmations leading to this type of reac-
tion should be avoided in pharmaceutical
practice
68 Dosage Form Design and Evaluation
Fats and fat'soluble vitamins are iisaally
dispersed m fine globules in the small intes>
Une by the emulsifying action of bile salts
This dispersion is a prerequisite for adequate
absorption Patients Vrho are unable to al^rb
fats properly may be aided by adimnistration
of surface active agents Emulsification and
dispersion of fats and bpoid substances such
as vitamm A arc thereby promoted and ab*
sorption is enhanced
^me apparently pharmacologic effects of
surfactants actually are due to a modification
of the physical properties of the dosage forms
m which they and the medicament are con-
tained For example, a group of investigators
have found that coadmmistration of poly-
sorbatc 80 with spironolactone yielded blo(^
levels of the latter which were as much as
four tunes higher than when spironolactone
was admmistcrcd alone Since the biologic
half life of the drug remained the same, it
was concluded that polysorbatc 30 promoted
the mlnnsic gastrointestinal absorption of
spironolactone However, this conclusion
proved to be erroneous in subsequent expen
ments and bad to be withdrawn, since mere
modificauon of the physical properties of the
tablets had similar effects The surfactant
acted in this instance on the dosage form itself
and modified its drug release properties
(This example will be discussed further in
the section devoted to pharmaceutical fonnu
lation factors )
Some effects that arc apparently specific
and limited to particular surfacc-activc agents
deserve mention It had been found that poly-
sorbatc 80 poI)sorbatc 85 and G 1096
(polyoxyethylene sorbitan hexaoleate), when
administered undiluted in high doses, co
hanced the gastroinlesunal absorption of
Vitamm Bu by rats A number of other
surfactants did not have this enhancing effccL
Further examination revealed that the three
effective agents formed a highly viscous mass
when mued with gastric fluids, while the in-
cflccuve surfactants did noL The absorption-
enhancing activity of the three ‘ effective ’
surfactants could be attnbuted to retardation
of gastric emptying, as shown by additional
experunents Naturally, the conditions of the
experiments were completely unpbysiolopc
and ore not applicable to human therapy
Many of the pharmacologic mvestigations of
surface active agents mvolvc the admmistra-
tion of extraordinarily high doses, and the
results should not be extrapolated rouUnely
to clmical conditions In mterpretmg labcn
ratory observations, particular emphasis must
be placed on the doses or the concentrations
employed, especially if the surfactant effect
IS on the biologic membrane
Dioctyl sodium sulfosuccmate is another
surfactant which exerts a pharmacologic
effect which is apparently specific to this par-
ticular agent rather than bemg shared by all
other surfactants It retards gastnc empty-
ing and has a powerful inhibitory effect on
gastnc secretions, even when administered m
relatively low doses Intcrcstmgly enough,
inhibition of gastric secretions occurs when
the drug is administered intraduodenally, but
there IS no effect when contact of the drug
IS bmited to the lumen of the stomach or
when It IS administered parenterally It has
been suggested that the mhibitory effect of
dioctyl sodium sulfosuccmaie is mediated by
a hormone released from the mtestmal mu
cosa, c g., cnierogastrone
Dioctyl sodium sulfosuccmate as well as
another anionic surfactant, sodium lauryl
sulfate, enhances the absorption of the am-
omc dye phenol red from the colon of the
rat, while a noniomc surfactant does not
None of the three surfactants influenced the
absorption of a cationic dye, methyl violet
The mechanism of this effect is not quite
clear, since it could be inhibited by a gan-
glionic blocking agent or an anticholinergic
drug This suggests that an active biologic
process may be mvolvcd “•
In cvaluatmg the effect of surface-active
agents on the absorption rate of a drug, it is
essential to establiih whether this effect is
mediated through on alteration of the absorb-
ing membrane, an mteraction with the drug
or a modification of the physical properties
of the dosage form. A change m the perme-
ability characteruucs of the absorbmg mem-
brane may be noted by any change m the
absorption of substances uhich are known
not to interact with the surfactant (provided
that dosage form effects are ruled out by
administering the drug m solution) MiccUu-
lar solubilization is dctcrmmable by equi-
Pharmaceutical Formulation Factors
69
Ubnum dialysis’-*^ and solubility methods,'
while dosage form effects can be established
by means of dissolution rate studies In this
manner it is generally possible to obtam an
understandmg of the nature of the surfactant
effect and thereby utilize surfactants mtelU-
gently to enhance the activity of drugs or to
avoid inhibitory effects by removmg the sur-
factant from a formulation where this be-
comes necessary As m the case of complcxa-
tion reactions m general the absorption
inhibitmg effects of surfactants can be ex-
pected to be most noticeable m dosage forms
which are not diluted extensively by body
fluids on admmistratioa
PHARMACEUTICAL FORMULATION
FACTORS
The pharmacologic and physical-chemical
considerations concerning the development
and the evaluation of pharmaceutical dosage
forms, which have been outlined in the previ-
ous sections, represent the necessary founda-
tion lor a review of pharmaceutical formu-
lation factors Many of the subjects discussed
m the previous section could as readily be
included here, but they have been grouped
separately for better clarity of presentation
This section deals primarily with a considera-
tion of biophaimaceutical aspects of the
more important classes of pharmaceutic^
preparations and outlines some of the prob-
lems that may be encountered with certain
of these The effect of phannaceulicai for-
mulation factors on the therapeutic eflSca^
of drugs has been reviewed and illustrated
recently by examples from climcal and
scientific literature It is hoped that
the reader will refer to these articles, because
the present section will be more concerned
with the reasons why and the mechanisms by
which pharmaceutical formulation factors
can modify the therapeutic efficacy of drugs
The major classes of pharmaceutical dos-
age forms designed for internal use may be
listed m a sequence representing the order
of rate of release of their active ingrcdienls
With reference to this sequence, it is assumed
that the active medicinal is stable in gastro-
intestinal fluids Reversals within the se-
quence may occur m cases where a drug is
unstable m gastric fluids The reasons for
this possible reversal have been discussed
earlier m the subsection devoted to stability
Furthermore, the sequence is based on the
usual properties of the listed classes of prep-
amtions, and it should be clear that excep-
tions may occur in specific mstances Emul-
sions, nonaqueous solutions, sustained release
dosage forms, aerosols and suppositories are
not listed above, because they represent more
complicated systems which do not lend them-
selves to ready classification and which must
be as^ssed individually
LiQuros
Drugs are absorbed from the gastrointesti-
nal tract most promptly when administered
m aqueous solution ^lubility limitations,
poor stability, objectionable taste and eco-
noouc considerations may require the use of
other dosage forms, but, m the absence of
such deterrents, aqueous soluuons represent
the dosage form of choice when rapid and
predictable absorpuoo is desired Homologs,
when administered m tablet form may differ
m rate of absorption because of differences
m their intrinsic rate of dissolution, but these
differences are not operational when the com-
pounds are admmislered already in solution
For example, potassium peniciUm V gave
higher blood levels than benzathine penicil-
Im V when both were administered m tablet
form, but solutions of the two drugs yielded
essentially equal blood levels of penicillin
This could be attributed to differences m the
dissolution rales of these substances and to
Uieir apparently similar intrinsic absorption
rates
It IS obvious that liquids are easier to
swallow than solid dosage forms and that, for
this reason, solutions are often preferred m
pediatnc and genatnc medicine However,
there is an interesting example of a case in
which the solution dosage form is particularly
indicated in a certain type of pathology The
gastrointeslmal absorption of calaum after
Aqueous SoluUoo — Suspension — Powder — Capsule — Tablet — Coated Tablet
< - .. - .. — (increasing rate of release)
70 Dosage Form Design and Evaluation
Fio 29 Average blood lc\cls of free
sulfonamide in children following oral
adnumstration of sulfadimeihoxine (I
Cm/M^) in tablets and m suspension
(Alter Sikuma, T e/ at Am J Med
Sci 239 142)
ndmuiistration of edetuat carbonate and a
solution of calcium citrate, respectively, was
compared m healthy subjects and m anacid
subjects The results of the study are sum
manzed m Table 8, where the area under the
calcium serum level vs tune curve is mdica*
live of the relative omounis of calcium ab*
sorbed
Calcium carbonate dissolves in acidic gas*
tnc fluids to yield calcium ion m absorbable
form. Individuals who do not produce gastric
hydrochloric acid arc unable to dissolve sig
niiican! amounts of the drug This accounts
for the very poor absorption of calcium by
anacid subjects after administration of cal-
cium carbonate powder When calcium was
administered m the form of calcium citrate
solution, the gaslrointcslina] absoipJion by
anacid subjects was considerably increased
However, It was not as high as in normal sub-
jects, probably because some of the drug pre-
cipitated m the absence of an acidic environ-
ment in the stomach and the proximal small
intestine of the anacid subjects Chelation of
calcium with citrate had no apparent effect
as such on absorption rate, as evidenced by
essentially identical scrum levels at all times
after administration of the two forms of cal-
cium to normal subjects These observations
should apply also to other acid soluble drugs
which are insoluble or poorly soluble in neu-
tral or allalinc fluids
Viscosity-cnhancmg agents arc sometimes
included m solutions to modify consistency
Table 8 Gastrointestinal Absorption
OP Calcium by Normal Subjects and by
Anacid Svbjects after Administration
OF Calcium Carbonate Powder and Cal-
cium Citrate Solution in Equivalent
Doses*
Average Area under
Serum Level vs
Time Curve
( in rag % ‘hr)
Calcium Calcium
Carbonate Citrate Sol
Nonnal subjects
Anacid subjects
447 477
0 87 2 75t
•NjfpnMUJD, W Kill? WftrJjenscJir JP J064
t Average of 13 subjects all other values are
averages of 10 subjects
andpourabiJity Of course, they are routinely
used m suspensions to obtam greater physic^
stability If the concentrations of suspending
agent and the administered dose are suffi-
ciently high so as to maintain a relatively
high viscosity even on dilution of the prep-
arauon m the gastrointcstmal tract, drug ab*
sorption may be retarded This is shown by
the data m Table 9, which lists plasma and
bram mnceotrations of salicylate after oral
adnuntstrauon of sodium salicylate solution
with and without 2 per cent methylcellulose,
sodium acctylsolicylate solution, and acetyl*
salicylic acid suspension contaimng 2 per
cent mclhylcchuJosc The volume adminis-
tered in each ease was 0 2 ml per 100 Gm
of body weight It is likely that high viscosity
was Uie major reason for the lower blood
levels obtained with the sodium sali^late
sciaiioa conlmaiDg meihyJrcfluJose, although
some complcxaiion cannot be ruled out In
the cose of acetylsalicylic acid suspension,
viscosity as well as dissolution rate would be
a factor limiting absorption The viscosity
effect IS due to the inverse relationship be-
tween the rale of diffusion of drug molecules
to absorption sites and the viscosity of tlic
Quids m which diffusion takes place
Suspensions rank next to soIuDoos with
respect to the rate of release of their active
in^cdicnis because of the large surface area
of the dispersed solids Particle size is a
critical factor, faster dissolution and absorp-
tion being achieved by use of finer particles
The particle size of drug solids m suspensions
tends to increase with tune, due to dissolu*
Pharmaceuiicol Formulation Foctors 71
Table 9 Effect of Dosaob Form on GASTRoiNTEsnNAL Absorption
OF Salicylates by Rats*!
Acetylsaucylic
Sodium Salicyl-
Aero Suspension
ATE Solution
WITH 2%
Sodium
WITH 2%
Sodium
Metmylcel
Acetvlsaucylate
Methylcel-
Salicylate
LULOSE
SoLtmoN
LULOSE
Solution
Plasma concentrationt 132
201
162
208
Brain concentrations 11 6
19 6
13 3
21 1
* Dose 0 72 mmo} /kg data are averages of 12 rats per group
t Davidson C , et <i{ J Pharmacol Exper Thcrap 134 176
t In meg /ml as salicylic acid Vi hour after drug administration
§ In meg /Cm as salicylic acid H hour after drug administration
Uon of the smaller particles and deposition
of drug from solution on the larger particles
Such particle growth should be prevented or
retarded by means which have been de-
senbed®® The advantage of adrmnistering
poorly soluble drugs dispersed m suspension
rather than compacted m tablets is exempli-
fied by a study of sulfadmietbowne absorp-
tion {See Fig 29 ) The drug was absorb^
much more rapidly and more completely
when administered m microcrystallme sus-
pension
Xateractions between active ingredients and
pharmaceutical adjuncts are particularly difli-
cult to notice m opaque suspensions, and the
possibility of such occurrences muse be con-
sidered carefully For example, sodium car-
boxymethylcellulose reacts with amphelammc
to form an even less soluble and less rapidly
available substance than amphetamine it-
self^’’ The use of sodium carboxymethyl-
cellulo&e to suspend amphetamine would
therefore be contraindicated The same may
apply to many other weak organic bases
There is sometimes the choice cither of
formulatmg a sparmgly water soluble drug
m aqueous suspension or of dissolving it in
an organic solvent If the organic solvent is
water miscible, such as ^yeerm, dilution of
the solution with gastrointestinal fluids may
not cause precipitaUon of drug because of
the mereased total volume of liquid Pre-
cipitaUon can occur if the drug is very in-
soluble m water and the administered dose
IS high, but the precipitate is usually of very
small particle size, which favors rapid disso-
lution as some of the dissolved drug is re-
moved by absorption Dissolved drug is not
as readily available if the solvent is immisci-
ble with water (i e , an oil) The comparative
efficai^ of an aqueous suspension and a
solution of drug m an oil depends on the dis-
solution rate of the drug, its oil water parti-
tion coefBcient and the ease with which the
oil tends to disperse m the gastrointestinal
fluids (the Jailer factor relates to the inter-
facial area between oil and water phase,
larger contact area promotes diffusion of drug
bom one phase to another) In one recent
study It has been found that the activity of
vanous esters of testosterone, androstano-
lone, prednisone and prednisolone on oral
administration, as well as the activity of the
respective &ee steroids, was greater when
these drugs were administered m sesame oil
soluuoa ^ao when given in aqueous sus-
pension * While the mvesugators were unable
to offer an adequate explanation for their
findings. It appears that the rate of drug re-
lease from the oil to the gastrointestinal fluids
was higher than the rale of dissolution of the
solid drug particles contamed m the aqueous
suspensions
The availabihty of drugs contained m
emulsion dosage forms depends on whether
the drug is present pnmanly m the aqueous
or the oil phase and whether the emulsion is
an od m water or a water m-oil system It
may also depend on the particle size of the
dispersed phase The latter factor is also of
importance m the absorption of poorly ab-
sorbable hpids In one study, for example,
less than 10 per cent of unemulsificd liquid
paraffin was absorbed, but more than 30 per
cent was absorbed when the oil was admin-
istered la emulsified torza
Solids
The major factors that cau influence the
biologic avajabihty of drugs from powders
72 Dosage Form Design and Evafuahon
arc readily ideaUfiabte particle size, dtssO'
iution rate and possible interaction with other
medicinal com^nents or with diluents pres-
ent in the powder dosage form Significant
particle growth on aging docs not occur
unless the drug has a high vapor pressure
or the dosage form is exposed to moisture
Dissolution rate may be modified by appro-
pnatc choice of crystal form or solvate type,
where indicated The most common type of
interaction of drug with diluent involves ad-
sorption of the former on the latter The
availabihty of adsorbed drug can be reduced
markedly if the diluent is water-insoluble and
a powerful adsorbent
A previously cited example, namely that
of spironolactone, may be enlarged on to
illustrate the effect of particle size on the
biologic availability of a drug with low in-
trinsic dissolution rate A recent study*^ per-
mits comparison of the relative biologic avail-
ability of spironolactone when administered
as a loose, encapsulated powder or when
compacted m highly-compressed tablets The
amount of spironolactone absorbed from
powdered drug mixed with lactose and en-
capsulated in gelatin capsules was found to
be 6 6 tunes as large as the amount absorbed
from highly compressed commercial spirono-
lactone tablets Administration of micronizcd
spironolactone resulted m the absorption of
10 times as much drug as from the com-
mercially available tablets Tlius, microniza-
tion improves the absorption from the gastro-
intcsunal tract so that 40 mg give the same
blood level * time values as 400 mg m the
form of coovcntional tablets Seme of these
data are shown m Figure 30
A unique technic has been dc\ eloped re-
cently by Japanese pharmaceutical scientists,
to cause sparingly water-soluble drugs to be-
come dispened finely m gastromtesunal
fluids * 2 This technic mvoUcs the formation
of a cutcctic rmxtuic of the drug and a phar-
macologically mactivc, readily soluble com-
pound The cutccuc mixture must ba>e a
melting pomt that is higher than room tem-
perature The two substances arc melted and
mixed, the rmxturc is cooled until it solidifies
and then is finely powdered When placed m
water, the readily soluble earner substance
dissolves rapidly and releases extremely fine
parlidcs of the drug. By using a eulccuc mix-
ture of sulfathiazolc and urea, it was possible
to achieve higher blood levels and earlier
concentration peaks of the sulfonamide than
are obtained by administration of orduiary
sulfathtazole
Relardatjon of drug release and a rcsult-
uig decrease m biologic availability due to
adsorption of the drug on diluents has been
observ cd with thiamine as well os other drugs
Some years ago, an acid-clay adsorbate of
ihiamme served as an international standard
for the bioassay of this vitamin Subsequent
studies revealed that the adsorbate actually
contained twice as much thiamine as was be-
lieved to be present on the basis of its anti-
neunUc activity m rats'** In other words,
only one half of the adsorbed vitamin was
biologically available under the cxpcnmental
conditions In another study, only 40 per cent
of the thiamine and 79 per cent of the ribo-
flavin ui Vitamin B complex capsules con-
taining fuller's earth were available to human
lest subjects Adsorption of vitawws
on msoluble diluents can reduce their avail-
ability so seriously that several scientists
associated with the Food and Drug Adnunis-
iration have suggested that the vitamin con-
tent of phannaceuueal products be evaluated
for labeling purposes on the basis of physio-
logic availability **
All the factors mentioned above also apply
to capsule dosage forms Au additional fac-
tor m the case of capsules is the dissolution
rate of the capsule shell Hard gclaUn cap-
sules dissolve quite readily m gastromtesunal
fluids, but a small diilcrcncc between the ab-
soipuon rate of drugs administered m powder
form, on one hand, and in gelatin capsules,
on the other, has been observed Soft gela-
tin capsules often dissolve more slowly than
hard gclaun capsules The former, if poorly
formiflatcd, may interfere with the prompt
absorpuon of their acUve mgrcdicnts In one
study, vitamm Bis was less completely ab-
sorbed from soft gelatin capsules than from
soIuUon*^ This may have been due to the
slow dissoluuon of the capsule shells Adsorp-
tion of drug on fillers and diluents can occur
with capsules as well as with powders Chem-
ical mtcracuon between components, though
rare in the absence of moisture, can occur
during dissolution This accounted for the
absorption retarding cflcci of diealcium phos-
Pharmaceutical Formulation Factors 73
phate when this substance was used as a
diluent m commercial tetracyclme capsules
Compressed tablets, which are the most
widely used dosage forms, also present some
of the most difficult problems with respect
to the biologic availability of their active m-
gredients fii commenting on the marked
effect of tablet properties on the rate of ab-
sorption of various penicillins, Juncher and
Raaschou concluded that “many published
studies that do not describe the pharmaceu
tical properties of the preparations used can
hardly be considered mdicative of an esti-
mate of the resorption of the pemcillm com-
pounds concerned ” * They point out that
‘this affords an explanation of many dis-
crepant results and conclusions in studies on
the oral admmistration of penicillin ” *
The major problem encountered with com-
pressed tablets IS due to the decrease in the
effective surface area of the active ingredients
as a result of granulation and compression
of the drug particles Availability of drugs m
tablets can W affected seriously unless this
process of compaction is readily re>ersible
when the tablets come into contact with gas-
tromtestmal fluids This reversal involves
usually the dismtegration of compressed tab-
lets mto their constituent granules, followed
by disintegration of the granules into primary
particles The primary particles dissolve at a
rate which is a function of their specific sur-
face area, their intrinsic dissolution rate and
the nature of their immediate environment
If a tablet fads to disintegrate, the surface
avadable for dissolution is limited to the
surface area of the tablet as such Disintegra-
tion of the tablets but not of the constituent
granules yields an avadable surface area
which, though larger than that of the intact
tablets, IS considerably smaller than that ob-
tamable by complete dismtegration of the
tablet and its constituent granules into pri-
mary particles
The foregomg comments should mdicale
to the reader that the intentions of those who
recommended adoption of the presently offi-
cial tablet disintegration test (namely, “lo
insure to the user of the tablet the ultimate
avadabdity of the medication and m such
•Juncher, H, and Raaschou, F The soJubiliiy
of oral preparalioos of penicillin V, AntibioC Med.
CUn. Thersp 4 497 , 1957
sm4
2 4 • •
Fio 30 Plasmalevels of spironolactone
metaboLte after administratioa of 400 mg
of spironolactone in commercially avad-
able tablets (•), 100 mg of powdered
drug m gelatin capsules (0)>aQd 100 mg
of microDized drug m gelatin capsules
(X) (After Bauer, G , er aL Arrneim -
Forsch 12 487)
reasonable tune as the nature of the medica-
tion might warTant”'t) cannot be realized
by such a test The fact that a tablet disin-
tegrates promptly mto granules does not as-
sure subsequent disintegration of the gran-
ules and dissolution of the primary drug
particles It w not too difficult to prepare
tablets out of crushed glass particles, for in-
stance, m a manner which permits such tab-
lets to pass th& U SP tablet dismtegration
test This test, though it represents a com-
mendable attempt to establish m minuim
avadabdity standards for compressed tablets,
can no longer be considered useful for this
purpose m the light of present knowledge
Tablet dismtegration may determme dis-
solution rate i£ it is the sloivest process m
the sequence tablet disintegration *
granule dismtegration — > particle dissolu-
tion A tablet dismtegration test could be
t Vlict, E B Tablet duinlegrauoa tests. Drug
;bAUiedlnd.-/2 17, 1956
74 Dosage Form Design and Evoluabon
INFLUIMCC DlSlNTtOKATlON TIME Of TABLETS OM
AVAILABIUTY OF PENICILUN V FOR ASSOWTION
Fia 31 From Nelson, E. Therapeutic
considerations of generic name presenp-
lions, Western Pharm 7J 9
indicative of the release rate of the active
constituents under these relatively rare
conditions Such a case has been reported
by Juncher and Raaschou, v,ho found that
the absorption of potassium pemciUin V
administered m compressed tablets was m>
flucnced markedly by the dismtcgration tune
of the tablets Using these data, and assum>
mg complete availability of the drug from the
most rapidly dismtcgratmg tablets. Nelson
constructed the graph shown as Figure 31
It indicates that, u this instance, potassium
penicillin V tablets could pass the US P tab*
let disintegration test even when one third of
their drug contents was not biologically
available
The more commonly occurring lack of
correlation between tablet disintegration tune
and rate of gastromtcstmal absorption of the
active ingredient is shown m Table 10 for a
senes of commercial aspirin tablets These
studies, earned out in ^e author’s labora-
toiy, demonstrate that dissolution rate, rather
than dismtegratjon time, is indicative of the
rate of absorption of ospirm from compressed
tablets The predictive value of m-viiro
dissolution tests, when calibrated against m-
vivo data, is evidenced by the go^ linear
correlation between the two (Fig 32)
Schrocter and colleagues undertook an ex*
tensive study of the possible relationship bC'
tween rate of dissolution and disintegration
time of compressed tablets.’*® They found
some cases where a relationship exists and
others where it docs not Correlations found
were highly specific and depended not only
on the t^pc of drug but, m some eases, also
Fjo 32 CoiTcIatioa of in vitro dissolu*
non rates and gastrointestinal absorption
of aspinn from vanous brands of com-
pressed tablets (cf Table 10) (From
Levy G J Pharm. Sci JO 388)
on the nature of pharmaceutical adjuvants
m the tablets These considerations limit the
tablet disintegration test to manufactunng
control purposes only and preclude its ra-
tional use as an official availahility test.
Recognition of dissolution rate rather than
disintegration time as the tablet property of
importance with respect to drug availability
from compressed tablets requued re-examma-
tion of ccrlam aspects of tablet formulation
It became necessary to dctcmunc the effect
of formulation factors, such as the type and
the concentration of dismtcgrant, bmder,
filler and lubricant, and the compression pres-
sure, on tablet dissolution rate
DissoluUon rate usually is decreased when
tablet compression pressure is increased
This is due to the more difficult disintegra-
tion of highly compressed particle aggre-
gates However, dissoluUon rate actually may
be mcrcosed when the drug solids are ex-
posed to extremely high pressure, because
of fracturmg of drug paruclcs and the re-
sultant mcrcase m their specific surface
area.’** Qunprcssion pressure has no effect
on the dissolution rate of nondismtcgratiog
drug solids’**
Dissolution rate is mcrcased as the con-
centration of starch, the most commonly used
Pharmaceutical Formulation Factors 75
Table 10 Disintegration, Dissolution and Gastrointestinal Absorption
Values for a Series of Commercial Aspirin Tablets*
Product
Average U S P
Disintegration
Time (Seconds)
Average Amount
Dissolved in
10 Minutes (mg )
Amount Excreted
INURINE t
(MO)
A
256
242
24 31
C
<10
165
18 1 [study It
E
<10
127
15 9j
B
35
205
1851
D
13
158
13 6 [study lit
E
<10
127
nil
* Levy, G Compamoa of dissolutioa aad absorpuoa r^es o{ dL^erent cocnmerctal aspina tablets,
J Pharm Sci SO 388
t la terms of apparent salicylic acid, 1 hour after admnustration of two D 3 Gm tablets
t Studies 1 and II were earned out with ditfereat test subjects and under somewhat ditlereat cotidiuons
dismtegrant, is increased Tablet binders
ordinary tend to retard dissolution, because
they delay disintegration and form a layer of
VISCOUS solution around dissolvmg drug
solids. Dissolution rate is also inversely pro*
portiooal to granule size if the granules are
nondisintegrating Certaui vitamins are
prepared m coated granules for inclusion m
conventional and “chewable” tablets These
pantiles are coated with Iipid or other ma*
tenals to overcome stability problems or ob-
jectionable taste Unfortunately, it has been
found that a number of commercial vitamin
products containing this type of granules did
not release their full contents of vitamins on
oral ingestion Caution and adequate in-
vivo evaluation of coated granules and of
preparations containing these is mdicated
Tablet lubricants are substances which are
mostly water-msoluble and water repellent
They can prevent adequate contact between
drug solids and dissolution medium One of
the few good waler*soluble tablet lubricants
IS sodium lauryl sulfate It has the further
advantage of being a surface-active agent
that actually promotes contact between drug
solids and aqueous medium and furthers
penetration of solvent into agglomerates of
solid particles The dissolution-retarding
effect of a hydrophobic tablet lubricant (mag-
nesium stearate) and the pronounced dtssolu-
uoQ-enhanemg effect of sodium lauryl sulfate
IS evident m Figure 33, which is based on
results of studies earned out m the author’s
laboratory It is this type of effect, rather
than the proposed absorption enhancement.
which undoubtedly accounted for the greater
absorption of spironolactone &om tablets
containing polysorbate 80,** as already mdi-
cated m the subsection on surface active
agents
Considerable research effort is still needed
to obtain a greater understanding of the vari-
» 10 0 20
Fio 33 Effect of lubncant on dissolu
tion rate of salicylic acid from compressed
tablets (X) Magoesium stearate 3%
(•) no lubncant, (O) sodium lauryl sul-
fate 3% (From Levy, G , f/ a/ jEffectof
certain tablet formulation factors on dis-
soIuUaQ rate of the active mgredicnt,
J Pharm Sci , in press )
76 Dotage Form Detign and Evaluahoa
ous formulation factors that can affect the
therapeutic efficacy of drugs contained m
compressed tablets Currently, phaimaccuu-
cal scientists arc particularly concerned uith
the development of suitable in Mtro dissolu-
tion tests and their correlation Vrith m \ivo
results An mtctcstmg and unique approach
to the study of dissolution of drugs from tab-
lets IS the use of thermal analysis which per-
mits continuous monitormg of the total sur-
face area of a dissolving tablet on the basis
of the beat c\olvcd due to the dissolution
process
The biopbarmaceutical problems associ-
ated with coated tablets arc so numerous and
so complex that they cannot be dealt with
adequately m a general review of this type
An excellent presentation of the subject ts
available elsewhere ***
CLINICAL EVALUATION OF
DOSAGE FORMS
Pharmacists must be aware of the more
important aspects of clinical evaluation of
drugs and particularly of the valuation of
new formulations and dosage forms The
community and the hospital pharmacist will
have to be able to read criucally and judge
the significance of research reports which
appear m the clinical Utcraturc or arc in-
corporated m manufacturers’ brochures, if
they want to assist physicians m the choice
of dosage form and manufacturers' brand of
therapeutic agents This requires knowledge
of the fundamentals of expenmentai design
and sfaCistical methodology Pharmacists can
also play an unportant port m the design of
clmical studies and m tiic evaluation of Tesvdts
denved from such studies if pharmaceutical
factors arc involved to the extent that the
clmicol data may be significantly inQucnccd
by them. It is up to the pharmacist to point
out certain variables which may not be con-
sidered ordinanly by the clinical mvestiga
tors, such as differences in salt form, particle
sac, vehicle and other formulation and dos-
age form properties of the therapeutic agents
to be studied Similarly, pharmacists should
be able to aid physicians m the evaluation of
research reports where biophormaccutical
factors may have aficeted the results The
research and the manufactunng pharmacist
is even more directly concerned with clinical
evaluation, since new dosage forms and for-
mulations developed by him usually require
clmical tnal to assess their eOicacy or defi-
ciencies
lliere is no standard methodology which
is applicable to the clinical cvaluauon of
every conceivable drug and its several dosage
forms The purpose of the study, as well as
the known or the expected pharmacologic
and pharmaceutical properties of a given
drug or formulation, will dictate the expen-
mental design Therefore, the research phar-
macist must be involved directly in both the
design and the interpretation of results of
ebn^ studies of dosage forms and formu-
latioos He will have to acquire competence
much beyond that which can be obtained
from the following paragraphs, which can
provide only an outline of the subject
Objectivcvs Subjective
Test Methods
Fortunately, most aspects of dosage form
evaluation permit the use of objective meth-
ods such as the determination of drug con-
centration m various body Quids This is so
because the therapeutic efficacy of the drug
as such has usually been established, and the
mam purpose is lo determine the degree to
which intrinsic absorpuon rate, availability
and elimination rate of the drug may have
been modified by the dosage form Whenever
possible. It IS desirable that dosage form
evaluation be based on quanuiauvc deter-
mination of the drug and/or its metabolites
m the bfood, the tissues or the unne Such
procedures arc least subject to bios and dif-
Icicnccs m intcrptmuon In some instances,
no specific assay method is available, or the
concentration of drug in the biologic Quids
IS too low for quaniitauvc measurement
Various pharmacologic parameters may tlicn
be used as indices of drug concentration, pro-
vided that the intensity of the pharmacologic
clTcct IS known to be a funcuon of drug con-
ccnirauon Thus, the physiologic availability
of a diurcuc agent may be assessed by the
volume of unne voided, and the absorption
of a mydnaiic by determination of pupil
diameter, but such values arc subject to con-
siderable vanatJon Therefore, these indirect
methods arc used only when direct methods
Clinico] Evaluation of Dosage Forms 77
are not available Evaluations based on sub-
jective methods are much more complicated
because the results depend to a considerable
degree on environmental and personal fac-
tors which may affect both investigator and
subject It IS difiicult to quantitate m a re-
producible manner such conditions as pam,
itching or nervousness and to evaluate dos-
age form effects on the basis of analgesia,
relief of itchmg and degree of tranquility
Experimental Design
Selection of Subjects. Pharmacodynamic
properties of drugs may often be studied in
healthy subjects, while determinations of
therapeutic efficacy require subjects suffering
from the disease for which the drug is con-
sidered to be indicated Thus, one may use
healthy subjects to determme the gastro-
intestinal absorption of an antibiotic, but
studies With anemic individuals are required
to verify the anti anemia activity of liver ex
tract It IS fortunate that dosage forms usu-
ally can be evaluated on healthy subjects,
because studies which require the use of pa-
tients suffenng from certain illnesses arc often
complicated by factors such as fluctuations
in the severity of their condition, the self-
limiting nature of certain diseases and the
difficulty of assembling a sufficient number
of patients with similar pathologic involve-
ments However, some drugs arc too toxic
to be evaluated in healthy volunteers For
instance, many cytotoxic agents used in the
treatment, of inahgnaTicics have extremeVy
unfavorable therapeutic indices so that their
pharmacodynamic evaluation m normal sub-
jects cannot be justified Absorption, bio-
transformation and elimination data obtamed
from studies using healthy subjects can pro-
vide useful comparative information about
certain dosage form effects, but it must be
recognized that these values frequently may
not be applicable in the quantitative sense to
subjects suffering from gastrointestinal, he-
patic or renal disease
Where the purpose of a study is the de-
termination of absolute rather than com-
parative values, such as the biologic half-hfc
of a given drug, the selection of a represen-
tative population sample becomes important
While the sample may be restricted arbitrarily
to a certain specified age, racial or geographic
group, the selection of subjects who are to
constitute this sample must be randomized
by means of available statistical technics so
that It may be representative of that total
population group
Controls. The purpose of using controls
as part of the expenmental design is to iso-
late the variable to be studied and to provide
a sound basis of companson A potential
sustained release medicament must be com-
pared With a conventional dosage form of
the same drug at the same dose if the sus-
tained release effect is to be demonstrated
The effectiveness of a topical antipruritic
agent can be assessed meaningfully only by
companson with the effect obtained from the
ointment or the lotion base alone, because the
latter may exert a soothing, cooling or protec-
tive effect and, thus, account entirely for the
efficacy of the preparation The use of con-
trols may not ho jxissible if it requires that
some severely ill pauenis remain unmedi-
cated, or if only a small number of unusual
cases are available, but, even then, an ad-
mittedly less satisfactory ‘ histoncal” control
IS implied, 1 e , the Tecollecuon of previous
cases treated differently However, in the
majority of instances and, particularly, m the
cimical ev^uation of dosage forms, the use of
adequate controls must be considered manda-
tory, and their absence will usually invalidate
the results of the study Despite this, pharma-
cists will frequently find reports of clinical
studies which are devoid of adequate controls,
as radicated by a recervt assessment of re-
search methods used m 103 scientific studies
reported in Canadian medical journals 35 5
per cent had no controls, 12 5 per cent had
inadequate controls and only 25 1 per cent
of the studies were considered to have been
well controlled The balance of the articles
dealt with studies where control was impos-
sible or mapplicable
Placebos. Placebos arc pharmacologically
men substances which are administered to
subjects who believe that they are receiving
an active drug This piermits distinguishing
between the effects of the drug proper and
the effects due to the act of administering it
Placebos are used primarily m therapeutic
tmis which arc based on an assessment of
subjective responses In dosage form cvalua-
Uoo, placebos arc necessary controls when
78 Dosage Form Design ond Evaluation
Table II Side Effects in a 16 Week,
Double-Blind Trial of GRisEoruLviN*
Patients
ffrcEiviio
GRlSEOrOLVlN
Symptoms (37)
PAOENIS
Receivisc
Inert
Tablets
(39)
Headache
3
I
Dy spcpsia
1
1
Abdominal discomfort 1
2
Vomiting nausea
0
2
Diarrhea
1
2
Ulcers m mouth
0
I
Cramps in limbs
2
0
Flushing of face
0
1
Drowsiness
0
I
Fever
1
0
Lassitude
1
0
Bnttle nails
0
1
Rashes or itching
3
4
'From Bell W and 5tevensoa, C / Report on
a cUmcal Inal uith gnseofulvio Tratu St John
Hosp Derm Soc
the incidence and the seventy of side effects
such as gastromiesUfia] irritation, nausea and
vomiting are to be established Without coo-
uols, one may get a {also unpccssiott of a
large number of side effects when, actually,
most of these arc not directly due to the drug,
0 $ shown m Table 1 1 **
While the substance constituting the pla-
cebo may be pharmacologically inert, the
process of admuiistcnng this substance as a
medicament may have both subjective and
objective pharmacologic effects, such as in-
creased gastnc hydrochloric acid secretion,
analgesia, relief of allergic symptoms, ctc^
The quantitative and the qualitative nature
of Uic placebo effect is largely influenced by
environmental conditions, mcludmg the alti-
tude of the investigator and the hopes, the
apprehensions and (he past expcncoccs of
the patient
Expcnmcntal Technics. In addition to the
use of controls and placebos where mdicatcd,
there are several cxpcnnicntaJ iccbnics which
ore utilized to overcome extraneous factors
which could affect the experimental results
In the sin^le-bhnd ledmic, the patient docs
not Vnow the identity of the medication so
that his response is not mfluenced by pre-
conceived notions or previous ctpcncoccs
In dosage form evaluation, this requires that
the vanous preparations should not be readily
differentiable on the basis of appearance,
taste and similar properties Thus, two tablet
formulations should not differ m size, shape
or impnnt When comparing a parenteral
form of a drug with a tablet form, it may be
necessary to admmistcr the parenteral me-
dicament and a placebo tablet m one mstance,
and the tablet contammg drug together with
a placebo injection such as sodium chloride
solution m the other instance The smglc-
bhnd technic is applicable when the subject’s
response may be affected by bias or sugges-
tive influences If the drug evaluation IS based
on objective parameters such as drug con-
cenirauon m the blood, the single-bJind tech-
nic IS not usually indicated
Where the pharmacodynamic properties
and effects of a drug cannot be measured
readily by objective methods but arc based
on impressions and qualitative assessments
by the mvesugator (for example, reduction
of mflatnmauon, improvement of a skin con-
dition or degree of tranquility), it is desirable
that neither (he subject nor die investigator
know the identity of the medicament. This
iskfiowm as the double blind techruc, in wbch
all medications arc coded and the code u not
broken until the study is concluded and the
data have been analyzed Uofortunatclyi
some drugs have side effects, taste or other
properties so characteristic and impossible
to conceal that the patient soon learns to
recognize them and only the investigator rc-
mams ‘ bhnd ”
There arc considerable differences between
subjects with respect to such physiologic fac-
tors as gastrointestinal motilily, body weight,
blood volume, etc If two dosage forms were
to be compared by administering them to
two different groups of individuals, the pos-
sible physiologic differences between these
two groups can complicate interpretation of
the experimental data Therefore, it is desir-
able to administer both dosage forms to each
subject This is known as the cross-o\er
technic and establishes a better control A
more sophisticated design is the double cross-
o\er technic, which involves a repetition of
the cross-over procedure so that each subject
receives both dosage forms twice The double
CTOss-over technic permits deicrmination of
reproducibility and indicates the degree of
imrasubjcct variation. It thereby results to
Clinical Evaluahon of Dosage Forms 79
Table 12 Sequence of Drug Adminis-
tration According to a Latin Square
Design
1 Evaluation of Two Drugs
Forms (Designated A and B)
OR Dosage
First
Period
Second
Period
Patient Group 1
A
B
Patient Group 2
B
A
2 Evaluation of Three Drugs
Forms (A, B and C)
OR Dosage
Fust
Second Thud
Period
Period Period
Patient Group 1
A
C
B
Patient Group 2
B
A
C
Patient Group 3
C
B
A
more valuable information and permits more
meaningful conclusions
Further refinements of the cross*over tech-
nics are obtamed by means of a latin-sguare
design, m which the sequence of drug ad-
ministration IS vaned Consider an ejpen
ment ui which dosage form A is to be com-
pared with dosage form B One may first
administer A to all subjects and, after an
appropriate time interval, follow it with B
This constitutes a cross-over Alternately,
one may divide the experimental subjects into
two groups, With Group 1 receiving A and
Group 2 receivmg B After an interval of
tune, drug B is administered to Group 1 and
drug A to Group 2 In this way the two
groups receise the drugs in different order
This design can be extended to more than
two drugs or dosage forms as shown sche
matically m Table 12 In this way, the order
of drug admmistration is eliminated as an
experimental variable which, potentially,
could infiuence the results For mstance, A
may cause gastrointestinal irritation which
makes the mucosa sufQcicntly sensitive to
react adversely to B despite the fact that B
ordinarily does not affect the gastrointestinal
mucosa to any significant degree The latin-
square design also serves to equalize certam
unrecognized factors which may influence
the experimental results, such os an unusu-
ally hot day, a malfunctiomng analytic in-
strument or a different laboratory tcc^cian
Experimental Conditions. Various expen-
mcntol candiuons can either enhance or sup-
press differences between dosage forms, so
that It IS important to be aware of the mech-
anisms which account for particular advan-
tageous or undesirable properties of the dos-
age forms studied If a drug is absorbed more
rapidly when admmistered m tablet formula-
lioa A than m tablet formulation B because
the former tablets dismtegrate more rapidly,
this effect will be noticeable only when the
tablets are swallowed whole and not chewed
If an alkaline additive enhances die gastro-
mtestmal absorption of a weakly acidic drug
by mcreasing the rate of dissolution of the
latter, the enhanemg effect will occur only if
the drug additive combmauon is adminis-
tered m solid form and not m solution Many
similar examples may be cited, but they all
mdicate merely that the choice of expen-
mental conditions as well as conclusions
drawn from the results of a cUnical evalua-
tion of dosage forms mast be based on a
thorough understanding of the biophanna-
ceutical facton and mechanism mvolved m
the dosage form effects
Dietary factors can influence markedly the
gastrointesimal absorption of certain drugs
Apparently, the amount of gnseofulvm, ab-
sorbed following oral administration can be
increased markedly by giving the patient a
meal high in faL^^ This is shown m Figure 34
Success of therapy may be affected decisively
by the patient’s dietary regunen, since made-
lOOfOFALOOSeS
Fic 34 Effects of different types of
food intake on the serum gmeofulvm
levels foUowuig a 1 0 Gm oral dose
(From Crounse, R. C J Invest. Dcrmat
37 529)
80
Dosage Form Design and Evoluohon
Fic 3S Scnirn concenuatioos after a
single oral dose of 300 mg of 7'«hloro>
6>^cmcthyUetrac)chne (•) on empty
stomach (O) with 20 ml of olummum
hydroxide gel (X) with Vi pim of whole
milL (After Schemer, J , er aL Surgery
IJ4 9)
quatc absorptiOQ of griseofulvin appears to be
one of the mechanisms of clinical unrespon
sivcncss to therapeutic doses of this drug The
gastromtestma! absorption of 7<hIoio-6
dcmcthyltctracyclinc and other tctrat^clmes
IS seriously impaired by simultaneous ingcs
tion of millk milk products or aluminum hy
droxidc gel Milk and antacids have been
prescribed by physicians to reduce gastro-
intestinal complaints associated with tetra-
cychne therapy Such practice and (he fower
tctracyclme blood levels rcsullmg therefrom
(Fig 35) may be responsible for some of the
therapeutic failures encountered with these
antibiotics
Methods of Dosage Form Evaluatio'*
Dosage forms and formulations are evalu-
ated usually with respect to one or more of
the following properties absorption rate,
stability m the gastromtcsunal tract, elimi-
nation rate, physiologic availability of the
therapeutic agent and incidence and severity
of side effects caused by the drug or other
onstitucnts of the dosage form In certain
more specialized cases it may be necessary
to extend the scope of the evaluation process
to such matters as tissue distnbution plasma
binding and sensitization liability, but these
Will not be discussed here
Gastrointestinal Absorption Rate. This
may be studied by determining the concen-
tration of the drug in the blood as a function
of time after drug administration In a com-
parative study, It may only be necessary to
compare the blood levels of drug when the
latter IS admmistcred m a given dosage form
With a suitable standard, such as the blood
levels obtained after administration of the
drug in aqueous solution fn an absolute
study, such as estimation of the inherent ab-
sorption rate of a new compound, the time
of peak drug concentration or the iniual rate
of increase of drug concentration m the blood
arc useful indicators of absorption rate When
the urinary excretion rate of the drug or its
mayor metabolite is a function of drug con-
centration in the blood, it is feasible to study
drug absorption by means of the urmary ex-
cretion mcihod.*®* This mvoivcs collec-
tion of total unne at regular intervals after
drug administration, and quantitative assay
of each portion with respect to the drug or
the major metabolite A cumulative plot of
amount excreted versus tunc may then be
constructed, from which average excretion
rates may be estimated by graphic methods
(Fig 36) Excretion rales can also be ob-
tained from the experimental data by mathc
matical technics If m a comparative study
different dosage forms affect urinary pH.
urine flow rate and drug bioirans/ormation
to different degrees, utilization of cither blood
sampling or unnaiy excretion methods as
sole indices of drug absorption may not be
sufficicDl, and both technics may have to be
used together
Hie onset of a characteristic pharma-
cologic effect, sucii as reduced salivary flow,
can serve as an index of drug absorption
rate Some drugs, such as potassium iodide,
ore concentrated m saliva in which they may
be determined chemically or by taste, so that
the time interval between drug administra-
tion and its appearance m the saliv-a can be
a useful mdicator of absorption rate Some-
tunes isotope labeled drugs may be admin-
Clinical Evoluahon of Dosage Forms 81
islered and their appearance and concentra-
tion build up monitored by measurements
of isotope activity at an extremity, such as
the hand, or at a site where the drug may be
come localized, such as the thyroid gland
(m the case of certam lodmated compounds)
Drug Stability m the Gastrointestinal Tract.
The efficacy of certain dosage forms depends
on protecting the therapeutic agent from the
degradativc effect of acidic gastnc fluids or
various en2ymes diat are present in the gas
tromtestmal tract In such studies it is paitic
ularly necessary that the drug assay method
be sufficiently specffic so that it niU distm
guish between the drug and its breakdown
products It IS often possible to obtain at feast
comparative mformation concerning the pro-
tective effect of dosage forms by in vitro ex-
periments, since degradative conditions such
as pH and enzyme concentration can be
duplicated relatively easily in the laboratory
and Since primarily ph)sicochemical rather
than biologic processes are involved
Elimination Rate. A large number of thera
peutic agents are eliminated from the body
at an apparent first order rate, which means
that the combmed effects of excretion and
biotransformation cause the disappearance
from the body of a constant fraction of drug
per unit time In some instances the elmit-
naiion rate is zero order i e , a constant
amount of drug is elimmated per unit time
Both rates may be descnbed by means of a
rate constant or m terms of half-life, which
is the tune required for the amount of drug
in the body to be reduced by 50 pet cent *
The elimination rale is reflected by the slope
of the declining portion of a drug concentra-
tion m the blood vs time plot and, fre-
quently, by the declining portion of an excre-
tion rate vs Ume plot, provided that decline
m the concentration or excretion rate is due
entirely to drug elimination and is not the
sum of drug elimmation and continued but
decreasing absorption The latter complica-
tion may lead to mismterpretations, particu
lady m the case of prolonged releiwe medi-
cation, where a slower rate of decline of drug
concentration in the blood (as compared with
• It Should be noled that the bait life is ujde-
pendent of concentniiion in first-order rate proc-
esses. but that It changes with conceotralioa la
zao-order rate processes.
creied vs time {below) (O) tetracyclme
faexametaphospbate cot^lex. {□) tetra
cycluje b)drocbIonde, (From Nelson, E
J Am. Phann Ass (Sci ) 48 96)
the concentration decime after admmistra
tion of drug m conventional form) is usually
due to further drug absorption and does not
sigrufy a longer biologic half life It is easiest
to determine elimmation rate after adminis-
tration of a drug by the mtravenous route,
after an initial rapid decline of drug concen-
tration m the blood due to equilibration with
other tissues, concentration vs time plots
usually yield straight lines on semiloganthmtc
(for first-order dcclme) or linear (for zero-
order decline) graph paper After intramus-
cular or oral adrnimstraUon, drug concen-
trations wiU first increase to a maximum
while absorption rate is higher than chmma-
tton rate and then decrease when elimination
rate exceeds absorption It is important to
assess elimination rate from that portion of
the concentration vs time curve whicdi no
longer mcludes any contribution due to fur-
ther absorption, ^mpletion of absorption
82 Dosage Form Design and Evaluation
IS usually evidenced by the linearity o£ the
concentration vs tune cur\c (when plotted
on semiloganthmic or linear graph paper)
at some tune beyond the tune of peak con-
centration Since the elunmation rate of a
drug as evidenced by its concentration de-
crease m body Quids is not necessarily iden-
tical with the rate of decline of its phar-
macologic activity, It may be desirable to
detcrmme the rate of disappearance of the
'pharmacologic effect This is possible only if
the pharmacologic effect can be measured
quanutatively, although a somewhat cruder
measure of disappearance rate can also be
obtained by estimating the duration of action
on an all-or none basis
Biologic Availability. When drugs are ad-
mmistered orally, it is always important to
determine whether they are absorbed com-
pletely The degree to which an orally ad-
imnistered drug is absorbed into the system
IS referred to as its biologic availability As
mentioned previously, a therapeutic agent
may not be fully biologically available tor
reasons such as a low inherent absorption
rate, slow dissolution rate, slow release from
a tablet matia, or because it is bound to
some nonabsorbable macromolecule Several
technics, both absolute and comparative, arc
available for the determination of biologic
availability If a drug is stable m the gastro
mtcstmal tract and is mhereoUy well ab-
sorbed, It ]$ possible to detenmne the pos-
sible adverse effect of slow dissolution rate
or other dosage form factors on biologic
availability by using a solution of the drag
as the standard for comparison The areas
undcc the blood Icvei v% tunc cueves ob-
tained after adimnistration of the drug in
solution and in a given dosage form should
be equal if availability is not reduced by dos-
age form effects If only a fracuon of the
drug IS absorbed when adrouustered m a par-
ticular dosage form, the per cent absorbed
may be estimated by the ratio of the respec-
tive areas under the concentration vs time
curves When there is some question con-
cerning the biologic availability of a drug
even when given m solution, it may be ncc-
cssaiy to use a parcntcrally administered
dose as the basts of comparison If tissue
distribution or biotransformation of the drug
diffeis With route of administration, such
comparison of areas under the blood level vs
time curves is not justiffed and can lead to er-
roneous conclusions Biologic availabihty is
estimated most commonly and readily by
^tcrmining the amount of drug and its bio-
transfonnation products which are excreted
m the tirme This also requires a standard of
comparison m most instances, because uri-
nary recovery is seldom quantitative, smee
some of the drug may be eliminated by other
routes (pulmonary, skm, biliary) or me-
tabolized to the pomt where it can no longer
be identified as to its ongm Quantitative re-
covery IS sometimes possible by means of
isotopic labeling and analysis of unne, sweat,
expired air and feces, but this complicated
methodology is rarely indicated or applicable
to human subjects In urinary recove^ studies
It IS necessary to contmuc collection of unne
samples for a sufficient time to assure com-
plete recovery of whatever fraction is elimi-
nated by this route This may require a num-
ber of days or even weeks, dependmg on the
rale of elimination Another technic which
may have to be used if the rate of elunma-
tton IS very low or if little or no character-
istic excretion products appear m the unne,
IS the fecal recovery method Obviously, drug
which is not absorbed will appear m the feces
and may be determined by suitable assay
methods The fcccs also may contam some
drug and, particularly, biotransformatjoa
products that were excreted in the bile and
not reabsorbed This possibility must be con-
sidered m the choice of the assay method
and m the analysis of the experimental data
Side-Effects. Therapeutic agents may elicit
bo^v systenwi asid fcical swii-cffccts Syrxemvi
effects are usually some function of drug
concentration in the body, while local effects
may have vanous causes, some of which arc
related to the dosage form m which the drug
IS administered If Die dosage form can affect
the incidence and the seventy of side effects
such as nausea, vomiting, gastrointestinal
bleeding or diarrhea, it is mandatory that
these effects be considereii la any evaluation
of new dosage forms The control m such
studies is usually a placebo, although one
dosage form may be compared with another
When evaluation is based on objective pa-
rameters, such as fecal blood content, it may
be feasible to use the unmcdicated subject as
Clinical Evaluation of Dosage Forms 63
his own control without administenng pla-
cebos Assessment of subjective side effects
usually IS extremely difficult, due to placebo
effects and many other extraneous mfluences,
and represents a challenge of great magni-
tude to the chmcai investigator who under-
takes the study, to the statistician trymg to
analyze the sigmffcance of the data and to
the pharmacist and the physician who must
utilize this information mtelligently m daily
practice
Sensitivity of the Expenmental Afetbod.
The success of many research efforts depends
largely on the specificity and the sensmvity
of the technics used Subtle deferences may
not be apparent, or the data may show so
much vnuation that observed differences are
statistically insignificant when the experimen-
tal methods or conditions are inadequate or
mappropnate Assay procedures may often
be made more specific by proper utilization
of separatory procedures such as solvent ex-
traction, chromatography and ion exchange
Adequate recovery of drug from the biologic
specimen must be demonstrated The actual
assay must be sufficiently discnnunating to
keep blank values low For studies involving
quantitative determinations of drug or bio-
transformation products m biologic fiuids or
tissues, It IS helpful, where possible, to ad
minister relatively high doses to the subjects
so that blank values are very small relative
to the values due to the drug itself When
pharmacologic criteria rather than chemical
assajs are used m the study, it is desirable
to choose a dosage which is m the sensitive
range of the dose response curve The rela
tionship between dose and response must be
established experimentally in order to indi
cate the sensitivity of the method When a
therapeutic agent is absorbed both by an
active process and by diffusion, different dos-
age forms should be compared at the same
dosage level, smee lower doses may be ab-
sorbed more rapidly than higher doses
Greater uniformity among the expenmectal
subjects often reduces the degree of vana-
liott in the experimental results It may be
necessary to use the same technician for all
analjses and clmical procedures Last but not
least, an increase m number of subjects will
usually lead to more representative and sig-
nificant results
Evaluatiov of Experimental Data
Statistical Analysis. Once the chmcai ob-
servations and measurements have been
completed, it is necessary to assemble and
sununanze the data, analyze the significance
of any differences between dosage forms or
other vanables studied and denve conclu-
sions It is important that the results of the
investigation be described m sufficient detail
to permit others to judge for themselves
whether the mvestigator's conclusions ate
justified Often it is not feasible to report
every single observation or analytic result
Instead, these are usually summarized m
terms of measures of central tendency, such
as the average or the mean, the mode and/or
the median values However, measures of
ixntral tendency do not mdicate the vana-
tioo withm the group of mdmdual data so
summarized Vanous measures of variation
or dispersion are used for this purpose The
simplest measure of vanation is the range,
1 e , the difference between the highest and
the lowest values A more useful measure
of vanation is the standard deviabon, smee
it notes cot merely the extreme (highest and
lowest) values but gives an indicauon of the
way m which the total number of individual
values are distributed around the average If
the individual values are normally distributed
around the average (i e , the number and the
magnitudes of positive differences from the
average are the same as the number and
the magmlude of negative differences), then
the range of values encompassed by the aver-
age dz one standard deviation includes about
two thirds of the total number of values
which make up the group The average it
two standard deviations will include about 95
per cent of all values Another commonly
used measure of vanation is variance, which
IS the square of the standard deviation
Without mfoimation concerning the varia-
tions of values within each ^oup, it is im-
possible to come to a reasonable judgment
concerning the significance of an average
value or the significance of differences be-
tween two or more average values A small
difference between two averages may be
more meaningful than a large difference, if
the mtemal vanauons are very small m the
first pair and very large in the second pair
84 Dosage Form Design and Evolualton
Any differences m results obtained from
different dosage forms, modes of treatment
or other variables may be either "ical” or
due to chance Vanous statistical tedmics
(such as Student’s ‘ t” test, the chi square
test and analysis of variance) are used to
determine the likchhood that observed dif-
ferences are due to chance This is expressed
in terms of a probability or “P ’ value A * P”
value of 0 OS or 95 per cent sigmfies that m
only 1 out of 20 cases will a d^erence have
occurred by chance alone A “P ' value of
0 I or 90 per cent shows that in 1 out of 10
cases the difference will have been due to
chance In most mstances, experunental dif-
ferences are considered significant if the cal-
culated “P" value IS less than 0 05 Thus,
statistics cannot “prove” differences to be
real or fortuitous, it can only establish the
odds concerning thor “realness” The con-
verse IS also true lack of statisucally sig-
nificant difference between two groups docs
not prove that these groups are equal or
identical More refined experimental technics
and/or a larger number of measurements
may ueli establish differences that are sta-
tistically significant On the other hand, nega-
tive data (i e , the absence of any significant
differences) acquire validity pnmanly on the
basis of the demonstrated sensitivity of the
cxpenmental method used It is not mtended
here to describe la detail various statistical
technics or designs Numerous excellent
books on statistics arc available for this
purpose
Validity of Conclusions. Even the most
sophisticated statistical analyses cannot guard
against wrong mteipretatjon of the cxpcri-
mCBfaJ data and ua/usuSed eonclusjons Tlie
mathematical manipulations cannot ordi-
narily cause an unrecognized variable to be
uncovered, nor can they prevent an over-
cnlhusiastic investigator from cxtrapobting
his results far beyond the confines of his ex-
perimental system It IS at this pomt that the
reader of any published research paper or
manufacturer’s brochure must be esjjcciaUy
on guard A few hjpothetio examples may
help to illustrate the problem
Example iVo. /. ft has been found that
sulbcstrol administered orally m the form of
a given brand of cntcric-coatcd tablets is
fully ph)sioiogically available, and it is con-
cluded that enteric-coated ublets may be
used without concern as to the possibility of
incomplete absoqjtion of stilbestrol Com-
ment This conclusion is unjustified because
there are large differences between brands
with respect to types of coating and stability
of the latter m gastrointestmd fluids The
conclusions apply only to the particular brand
of tablets used or even only to the particular
lot, if large lot to-lot differences exist
Example No 2 It iS shown Uiat salicylate
iflisotption is more rapid after oral adminis-
tration of tablets containing aspirm and phe-
nacetm than after administration of an equal
dose of aspirm m the form of pJain aspirm
tablets It is concluded that phenacetm en-
hances the gastromtcstmol absoiption of as-
pirin Comment This conclusion is incorrect
because the more rapid absorption from the
aspirm phenacetm tablets may be due to tab-
let formulation factors Perhaps aspirm par-
ticle size, lubricants, compression pressure
and dismicgrant were such as to result m
much more rapid dissolution of aspirm from
the aspinn phenacetm tablets than from the
plain aspirm tablets
Example No 3 The relative effectiveness
of cortisone and hydrocortisone as topical
anti-mflammatory agents was studied by
companng results obtained from lotions con-
taining vanous concentrations of these agents
suspended in the same vehicle According to
the expcnmcotal data, a f per cent cortisone
lotion IS equal m effectiveness to a 2 per cent
hydrocortisone lotion, and it is concluded
that cortisone is twice as effective as hydro-
cortisone Comment This unusual result may
be due to a difference m particle size between
the two drugs, cortisone may have been m
raicronizcd form while hydrocortisone was of
relatively large particle size The conclusions
are not justified because the variable to be
evaluated (the drug) was not isolated since
on additional variable (particle size) was
overlooked
Example No. 4. A new dcnvative of tetra-
cyclmc IS shown to yield considerably higlicr
blood levels on oral administration than
tetracycline itself On this basis, it is claimed
that ^e new derivative is better absorbed
and that, at equal doses, it would be more
effective than tetracycline Comment The
higher blood levels may be due to greater
plasma bmdmg, and drug concentration m
Sources of Infomotion 8.5
the tissues may actually be lower whea the
den^'ative is us^ StmQaiiy, the total amount
of drug absoibed from gastromtestmal
tract may be the same in each case, or may
e\ea be greater after administranon of the
less plasma bound tetraqcLne It must be
demonstrated, among other dungs, that the
new dens’atise is not bound to plasma pro-
teins to a greater extent than tetracycbne
Itself, before the conclusions can be accepted.
Hie h}'pothetic examples ated above Qltis-
tiale some (but not all possible) reasons 'why
certam conclusions derived from expen
mental data may be unjustified. There may be
other reasons, such as experimental condi-
tions and doses or modes of administration
bemg “unphjsiologic.” They may differ so
much from the us't^ dinical conditions that
results of the study may not be apphcable to
normal therapeutics
Finall) , assuming that experimental design
was flawless and that the significance of ob-
served differences is demonstrated impres-
sively by means of highly sophisticated sta-
tistical methods, one must still deade as to
the practical significance of the data. For
example, there ma) be vec) little advantage
assocated with a new denvative, 1 mg of
which is as activ e as 5 mg of the parent com
pound After all, both substances probably
end up m tablets of equal size However, tf
the data also show that the new denvative
has a more more favorable therapeutic mdex,
then the differences between parent com-
pound and derivative are significant not only
m the statistical sense but also m tenns of
practical application.
SOURCES OF INFORMATION’
The body of knowledge m the general area
of biopbannaceutics is growing so rapidly
that regular and mtensive perusal of the cur-
rent literature is necessoi} to keep up with
new developments Judgments and evalua-
tions of dosage forms and formulations must
be based on established facts, and these too
can only be obtamed throu^ a consistent
review of the literature For this purpose, the
pharmacist requires sources of information
quite different from and additional to those
that only list composition, mdicanons, dosage
schedule, side effects, etc. of propnetaiy
products Among the journals, books and
services which could serve as the basis for a
contmumg program of acquiring informatxin
which IS helpful in evnluaUng and di-^tgnTno
dosage forms are the following
Journal of Fharmaceotical Saences. Issued
monthly by the Amencan Pharmaceutical
Association, this journal contains many
ongmal research papers dealmg with the
pharmaceutical aspects of drug efficacy A
regular feature of each issue is a review
article m winch the more recent advances
m an area such as kmetics of drug absorp-
tion, sustamed release medicatioa or anti-
biotics IS summarized by an authority m the
field
Climcal Pharmacology and Therapeutics.
This IS the official publication of the Ameri-
can Tberapeobc Socie^ and is issued bi-
monthl) The journal contains articles on
aspects of clinical phanaacoteg), expenmea-
tal design and e> oluaiion of new drugs Regu-
larly featured is a Current Drug Therapy
Section in which a given pharmacologic cl^
of drugs IS review^ critically, os well as a
secuon ennUed Diseases of Medical Progress
which contains abstracts of papers on ad-
verse drug reactions
Journal of the Amencan Medical Asso-
ciation. Through th^ P^igcs of this publica-
tion, the Council on Drugs of the Amencan
Medical Association attempts to provide au-
thontativ e and unbiased information on drugs
and drug therapy As soon as practicable
after a drug is marketed, the Council issues
3 detailed, descnptive monograph This
monograph is known as the PreUtmruiry
Statement As additional informatioa about
the drug becomes available, it is published
m a column entitled Aew Drugs and Devel-
opments in Therapeutics The journal also
coDtams Council — sponsored articles on the
current status of therapy m the treatment of
vonous diseases, as well as articles on pre-
compounded combinations of two or more
active mgredients m which pros and cons
concemmg their appropriate role in therapy
are discussed. In addition, the journal fea-
tures an Annual Therapeutic Number con-
taining summaries of addiuons to iherapeuUc
knowledge accumulated m the previous year,
articles on the more fundamental aspects of
drug therapy and a review of information de-
86 Dosage Form Design and Evaluation
nved from the Register/ of Adverse Reac-
tions A considerable number of the articles
and monographs mentioned above are re-
pnntcd m the American Journal of Hospital
Pharmacy
Not and Nonoflicial Drugs (J B Lippm-
cott Co , Philadelphia, Penna } is an annual
publication, in book form, by the American
Medical Association’s Council on Drugs It
represents a compilation of available i^or-
mation on drugs, mcludmg their therapeutic,
prophylactic and diagnostic status, as evalu-
ated by the Council Each monograph is
prefaced by a Summaiy of Council Opimon,
which mcorporates comparisons with older,
srrrulai dra^ •whtntNtt possiWe
Drugs of Choice (C V Mosby Co , St
Louis, Mo ) , edited by Walter Modell, is
published every 2 years In this book, the
authors try to present a comprehensive and
criucal appraisd of all drugs m current use
Included m the discussions are results of
clinical tests and data concerning relative
potency, toxicity, modes of administration,
onset and duration of effect and side effects
One chapter deals with physical and chem-
ical considerations m the choice of drugs
Year Book of Drug Therapy (Year Book
Medical Publishers, Inc., Chicago 11, 111),
edited by Harry Beckman, consists of elm-
ical and experimental evaluations of drugs
and includes a chapter on drug reactions as
well as a special section m which the year’s
new drugs are evaluated cntically
Current Contents (published weekly by
the Institute for ScieotijGc Information, Phila-
delphia 3, Penna ) represents a unique serv-
ice which helps to overcome the difficulty
mhcrent m the fact that research papers deal-
mg with topics of biopharmaccutic^ mterest
arc scattered throughout numerous scientific
journals In this publication, the tables of
contents of over 600 foreign and domestic
chemical, biologic and pharmaco-medical
journals arc reproduced regularly Any arti-
cle of mterest can be looked up in the ap-
propriate journal which may be available in
the libranes of universities or hospitals m
the area, or reprmts may be requested di-
rectly from the authors For this purpose.
Current Contents contams m each issue a
listing of authors’ addresses The journal also
provides an ongmal article tear sheet service
through which any of the articles listed may
be purchased directly from the Institute for
Scientific Information
The Medical Letter on Drugs and Thera-
peutics (published biweekly by Drug and
Therapeutic Information, fne , New York
22, N Y ) can be likened to a physician’s
‘ Consumer’s Digest” It incorporates cnucal
comments concemmg claims made m manu-
facturers’ advertisements and brochures, eval-
uations of new products as compared with
more established drugs and assessments of
the significance of pubbshed studies con-
cemmg the efficacy of pharmaceutical prod
ucts The publishers periodically acqune
vanous brands of genencally identical drugs
and have these assayed by an independent
laboratory The results are published m the
form of a tabulation listmg manufacturer’s
name, assay data and price Since a drug may
adhere to all official standards and suU be
therapeutically madequate,'’* it should be
appreciated that the above tabulation is
most useful in revealmg definitely imrebable
brands without necessarily providing an in-
dication of therapeutic equivalence for those
brands which are found to satisfy official
standards
The above mentioned sources can bo used
readily as the core of a regular information-
gathenng program by community and hospi-
tal pharmacists These sources should be
supplemented with standard and well known
reference texts, such as the United States
Dispensatory and Remingtons Practice of
Phanmey The reader also is referred to the
Special Literature Number of the American
Journal of Hospital Pharmacy (Vol 18,
January 1961), which features articles on
utilization of literature, classification and
filing, as well as a comprehensive guide to
information sources for pharmacists
Apart from the need to keep abreast of
scientific developments in bis field, the phar-
macist must be able to utilize the literature
m order to find specific information concern-
ing stabibty, compatibility, pharmacologic
properties, assay methods and similar aspects
of a given drug This may require a formal
search covermg the bteraturc of the past 10
jeais or more Usually, such a search is
undertaken with the aid of mdiccs and ab-
stract journals which arc available m the
libraries of umvcrsitics and m larger pubbe
libraries The more important among these
References 87
are Chemical Abstracts, Index Medicus and
Biological Abstracts Readers interested m
leammg more about the subject are referred
to A Key to Pharmaceutical and Medianal
Chemistry Literature, a book published as
No 16 of the Advances in Chemistry Senes
by the American Chemical Society
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34 Cavallito, C J , and O Dell, T B Oral
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36 Chow, B F, Hsu, J M, Okuda, K,
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of several species, J Pharmacol Exp
Ther 134 176, 1961
47 Dayton, P G , Tarcan, Y , Chenkin, T ,
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48 Deutscb, M J , Schiaffino, S S , and loy,
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Sulfonojtuden bci Fruhgeborenen, Z ces
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50 Domagk, C Twenty five yean of sulfon-
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51 Douglas, J R , Baker, N P, and Long
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relationship between particle size and
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Am J Vet Res 20 201, 1959
52 Dowdle, E B , Sefaaebter, D , and
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53 Dragstedt, C A Oral medication with
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54 Ercoli, N , and Lewis, M N Studies on
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55 Ercoli, A., and Cardi, R 3 Keto
steroidal enol ethers Paradoxical de-
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746,1960
56 Erdman, C J , Gibson, W R , Martin,
J W, and Me)ers, D B The pharma-
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presented at National Meeting of Amen
can Pharmaceutical Association, Chicago,
Apnl 1961
57 Forth, W , and Seifen, E Dcr Einfluss
Referenc«s 89
von KompIexbUdnem auf die ®*Fe Re-
sorption am isoUerten Darm dcr Ratte,
Naunyn-Schmiedeberg s Arch exp Path.
241 556. 1961
58 Frain Bell, W , and Stevenson, C I Re
port on a clinical tnal with griseofulvin,
Trans St John Hosp Derm Soc 45 47,
1960
59 Francis, C C, and Knowlton, O C
Textbook of Anatomy and Physiology,
ed 2, p 479, St Louis, Mosby, 1950
60 Franklin, M , Rohse, W G , Huerga, J ,
and Kemp, C R, Chelate iron therapy,
JA.MA 166 1685. 1958
61 Frazer. A. C Lipide absorption, Voeding
16 535, 1955 (through Cbem. Abstr)
62. Frederick, K J Performance and prob
leirn of pharmaceutical suspemiom, J
Pharm Sci 50 531, 1961
63 Frostad, S Continued studies m con
centratioos of para aminosalicylic acid
(PAS) m the blood, Acta tuberc
pncumol scand 41 68, 1961
64 Gantt, C L., Gochmao. N , and
Dyniewicz, J M Effect of a detergent
on gastrointestinal absorption of a steroid,
Lancet J 486,1961
65 Gastrointestinal absorption of
spironolactone, Lancet I 1130, 1962
66 Garrett E R. Facile hydrolysis of p
chlorobenzaldoxune and its oral m
efficacy, / Pharm Set 51 410 1962
67 Gaumano, B , Lexow, D , and Ehrt, D
Zum Ablauf der Vitanun Bi Resorption
bei der Ratte, Biochem Z.332 449,1960
68 Gfaazal, A, and Wnght, H N Glycine
and glucuronic acid m sahcylate mtoxi
cation. Paper presented at First Inter-
natl Pbannacol Mtg , Stockholm,
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69 Glazko, A J , Ddl, W A , Kazeoko, A.
Wolf, L. M , and Carnes, H E. Physical
factors affecting the rate of absorption
of chloramphenicol esten, Anlibiot
Cbemother (Wash ) 8 516, 1958
70 Goodman, L S , and Gilman, A The
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71 Gordon, H A, and Bruckner Kardoss.
E Effect of normal microbial flora on
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72. Grossman, M I , Matsumoto, K. K , and
Lichtef, R J Fecal blood loss produced
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73 Gullino, P M, and Grantham, F H.
Studies on the exchange of fluids between
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74 Hamlin, W E , Nelson, E, Ballard,
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1962
75 Hansen, I A Bivalent metal lon effects
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76 Harper, N J Dnig latentiation, J hfed
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77 Hartiala, K Experimental studies of
gastrointestinal conjugation functions,
Biochem Pharmacol 6 82, 1961
78 Henderson, W R , Carleton, J , and Ham
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upon serum levels of methicillin. Am J
Med Sci 243 489, 1962
79 Herz, R., Jr, Taplcy, D F, and Ross,
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1961
80 Higuchi, T Some physical chemical
aspects of suspension formulation, J Am
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81 Hi^cbi. T , and Shelter, E The in
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1962
82. Hogben, C. A hf , Tocco, D J , Brodie,
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1959
83 Hogben, CAM The first common
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84 Hogben, C A M , Schanker, L. S ,
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85 Hotter, H How things get into cells,
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86 Honla, A The route of administration
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87 loglefinger, F J . and Abbott, W O
Intubation studies of the human small in
testine the diagnostic significance of
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motor disturbance, Am J Dig Dis 7
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88 Jaqucs, L B Anticoagulants, physiology
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89 Jones, C M , Culver, P J , Dnimmey,
G D , and Ryan, A B Mc^ificaUon of
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the use of an emulsifying agent, Ann Int
Med 29 1, 1948
90 Juncher, H , and Raaschou, F The solu*
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Antibiot Med 4 497, 1957
91 Kakemi, K , Anta, T , and Koizumi, T
Relation of Particle Size to Blood Con
centration following Oral Administraiion
of N* (5 Ethj’I 13 4 thiadiazol 2 yl)sul
famlomide, Yakugaku Zasshi 82 261,
1962
92 Kakemi K , Anta, T , and Ohashi, S
Absorption and excretion of cblor*
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symposium papers presented at the Na-
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1962
93 Kohn, K W Mediation of divalent metal
ions in the binding of tetracyclines to
macromoiccules Nature J9J 1156,1961
94 Kostenbauder, H D , PortnolT, J B , and
Swintosky, J V Control of urine pH
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lo humans. Paper 0 VI in booklet of pre
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Pharmaceutical Association, Las Vegas,
March 1962
95 Kruger Thicmer, E , and Bungcr, P
Kumulation und Toxizitat bci falscber
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96 Kunin, C M , and Finland, M Cluucal
pharmacology of the tetracycline aoti
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1961
97 Lack, L , and Weiner, I M Jrav/rro ab
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of rats and guinea pigs, Am J Physiol
200 313. 1961
98 Lagerluf, H O , Rudewald, M B , and
Perman, G The neutralization process
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99 Lastcr, L., and Ingclfinger, F J In
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100 Laza^, J , and Cooper, J Absorption,
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prolonged action drugs, J Pharm Sci 50
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101 Lee, C C , Froman, R O , Anderson,
R C , and Chen, K, K Gastnc and m-
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V and the free acid, Anlibiot Qicroo-
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102 Levine, R M. Blair, M R , and Clark,
B B Factors influencing the intestinal
absorption of certain monoquatemaiy
anticholinergic compounds with special
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nucol Exp Thcr 114 78, 1955
103 Levine, R R , and Spencer, A F Effect
of a phosphatido peptide fraction of in
tesUnal Ussue on the intcsfiiia] absorp
tion of a quaternary ammonium com-
pound, Biochcm Pharmacol 3 248
1961
104 Levy, G Comparison of dissolution and
absorption rates of different commercial
aspirin tablets, J Pharm Sci SO 388,
1961
105 ->■ ■ The effect of absorption rale
upon inter subject variation m drug ab-
sorption from the gastrointestinal tract,
to be published
J06 — ■ ■■ Unpublished research data
107 Levy, G , Antkowiak, J M , Gumtow,
R. H , and Procknal, J A Effect of
certain tablet formulation factors on dis-
solution rate of the active ingredient, to
be published
lOS Levy, C, Gumtow, R H, and Rutow-
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upon the gasliointcstmal absorpUon rate
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1961
109 Levy, G, and Hayes, B A. Physico-
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saficyfic acid controversy. New Engf /
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IJO Levy, G, and Knox, F G The bio-
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1961
1 1 1 Levy, C , and Nelson, E Pbarmaccuucal
formulaUon and therapeutic cfQcacy,
JAMA. 177 689,1961
112 United States Pharmacopeia and
NaUonal Formulary Standards, Food and
Drug Administration regulations, and the
quality of drugs, N Y State J Med 61
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1 13 Levy, G , and Procknal, J A Unusual
dissolution behavior due to film forma-
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114 Levy, C , and Sahli. B A Comparison
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of the gastroiotestmal absorption of
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salicylic acid in man, J Pharm Sci SI
58. 1962.
115 Lewis, R A., and Said, D Influences of
posture on gastnc function Absorption
of ^ucose and production of acid, Paper
presented at First Intematl Pharmacol
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1961
116 Liguon, V R,, Gigho, J J. Miller, E,
and Sullivan, R D Effects of different
dose schedules of amethoptenn on serum
and tissue concentrations and urinary ex
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3 34, 1962
1 17 Lish, P M Some pharmacologic effects
of dioctyl sodium sulfosuccinate on the
gastrointestinal tract of the rat, Gastro
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118 Lish, P M, and Weikel, J H , Jr In
ffuence of surfactants on absorption from
the colon, Toxicol Appl Pharmacol /
501, 1959
119 Lozinski, £ Physiological availability of
dicumarol, Cacad M A J 177, 1960
120 Macek, T J in Remingtons Practice
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121 Marcus, A. D Complexation mcom
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122 Moroxowich, W , Chulski, T , Hamlin,
W E Jones, P M, Northam J I,
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rates, solubilities and LTqo’s m mice of
some salts of benzphetaimne and
etryptamme, J Pharm. &i , m press
123 Morrison, A. B , and Campbell, J A.
Physiologic availability of nboSavin and
thiomme in Chewable vitamm products.
Am J Clm Nutr JO 212, 1962
124 Momson, A. B, Perusse, C B, and
Campbell, J A Physiologic availability
and in \uro release of nboflavtn in sus
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125 Mullins, J D, and Macek, T J Some
pharmaceutical properties of novobiocin,
J Am. Pharm. Assoc [Sci ] 49 245,
1960
126 Murphy, J , Casey, W , and Lasagna, L.
The effect of dosage regimen on the
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134 286 . 1961
127 Nelson, E. Comparative dissolution rates
of weak acids and tbeir sodium salts, J
Am. Pharm Ass ISci] 47 297, 1958
128 Dissolution rate of mixtures of
weak acids and tnbasic sodium pbos
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1958
129 Influence of dissolution rate and
surface on tetracycline absorption, J Am
Pharm Ass [Sci 148 96,1959
J30 Therapeutic considerations of
generic name prescriptions. Western
Pharmacy 9, 1961
131 Kinetics of drug absorption, dis
tribuUoQ metabolism and excretion, J
Pharm Sci SO 181, 1961
132 Nelson, E , Knoechel, E L., Hamhn,
W E , and Wagner, J G Influence of
the absorption rate of tolbutamide on the
rate of decline of blood sugar levels in
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1962
133 Nelson, E. Physicochemical factors in
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and its esters, Cbem Pharm. Bull 10
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135 Newbould, B B . and Kilpatnck, R
Long acting sulfonamides and protem
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136 Nicbolson, A E, Tucker, S J, and
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VI Blood and tmne concentrations from
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137 Niepmann, W Expcnmentelle Untcr
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138 Nikkda, E A Acetylation of p-amino-
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139 Nogami, H , Hasegawa, J , and Nakai, Y
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Studies on tablet dismte^tion of cal
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140 Noyes, A. A., and Whitney, W R The
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141 O Dell, G B Studies m Kemictenis I
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Effects of physicochemical state of Vita
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143 O’Reilly, I , and Nelson, E. Unnaxy ex
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145 Otobe, S Conjugation of glucuronic acid
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1960
146 Parrott, E. L, Wurstcr, D E, and
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Chop/er 3
Solid Dosage Forms
Eugene L. Parrott, Ph.D.*
Approximately two thirds of all prepara-
tions dispensed are soDd dosage forms Cur-
rent sobd dosage forms consist of powders,
divided powders, dusting powders, insuffla-
tion powders, granules, capsules and tablets
With the exception of the compressed tablets,
which are presenbed m approximately 50 per
cent of all prescriptions, these solid dosage
forms may be prepared extemporaneously at
the prescription counter Although each form
has distinctive characteristics, solid dosage
forms have several general advantages over
liquid medication
Solid dosage forms have a small bulk and
are easy to package, transport and store The
patient finds them convenient to cany on
his person m small contamers A gallon of
phenobarbital elixir is not portable from the
viewpoint of the patient, however, 505 30-
mg tablets contammg the same amount of
the drug may be earned without any serious
objection For administration of a liquid
medication a troublesome teaspoon is re-
quired.
Compounds must be in solution to elicit
the sensation of taste, consequently, taste is
more pronounced m a liquid than m a sohd
medication. Unpleasant tasting drugs are ad-
mmistered most easily m the solid state be-
cause the dosage form can be swallowed
rapidly before a significant amount of the
drug can dissolve in the oral cavity to pro-
duce an unpleasant taste With the use of
confectionary bases, flavors and sweetening
excipients m sohd cUisage forms, there is less
rejection of obnoxious tasting drugs in sohd
dosages than m a flavored hquid preparation
* Associate Professor of Pharmacy, Stale Uai-
Ntmiy of Iowa.
Many sohd dosage forms enclose the drug
within a shell or a coatmg which acts as a
mechanical barrier between the drug and the
taste buds, so that the flavor of the drug is
never expenenced by the patient
Predivided sohd dosage fonns provide an
accurate dose, since each dosage form repre-
sents one dose With hquid medication the
patient madveitenlly introduces variance m
dose due to the lack of uniformity m the size
of the teaspoon and m the extent to which
be fills each teaspoon
Solid dosage forms may be prepared of
many drugs that cannot be satisfactorily dis-
pensed m a hquid form Aspinn is rapidly
hydrolyzed m the presence of moisture, and,
to date, no satisfactory liquid preparation of
aspirm has been developed Because chemical
reactions at room temperature normally
occur m solution, a drug m the dry solid
state has a greater shelf-life or stabili^ than
m the hquid state, fncompstxbihties are less
evident m the dry state For example, m
Alka-Seltzer and Seidhtz powders acidic sub-
stances are blended with a bicarbonate, and
no reaction occurs while the mixture is dry
When the consumer places the medication m
water, a reaction occurs rapidly.
Sustamed release and delayed release of
medication has become popular m the past
few years The vast majonty of sustained re-
lease products marketed are sohd dosage
forms because controlled release technics
generally are more applicable to sohd than
to liquid medicaUon
particle size
In preparing a prcscnplion for a sohd
dosage form, all dru^ must be reduced to a
95
96 Solid Dosage Forms
fine state of subdivision before mixing The
fine particle size facilitates mixing and
permits a more homogencous^reparation,
assuring the patient of a imifoim dose
Therapeutic efficacy of a drug may be
ailected by the particle size Microcryst^lme
sulfadiazine given orally appears more
rapidly and m higher concentrations in the
blood than ordinary sulfadiazme ponder As
the particles of sulfadiazine arc reduced in
size, there is a greater specific surface area
Since the solution of a given weight of the
sulfadiazine is proportional to the exposed
surface, with an increased surface area there
is more rapid solution and increased absorp*
tion from ffie gastrointestinal tract, as shown
m Figure 37
Novobiocin also shows the effect of par-
ticle size on solution and absorption When
the crystallme ^id form of novobiocin is
given orally, practically no absorption occurs
as mdicated by blood levels If this antibiotic
is micronized or jprecipitated m a finely
divided amorphous Itorm, it becomes an effec-
tive oral drug The more effective absorption
of finer particles is especially important with
sparingly soluble drugs such as corticosteroid
and sulfa drugs This effect has been demon-
strated with arsenic tnoxide, calomel, Lente
Uetm, oxytetrac)clme and chloramphenicol
In the subsicvc ranges, physical properties
of solids are a function of particle size In the
colloid range, there is a decrease m melting
point and an mcreasc m solubiUty and vapor
pressure A particle must be in the order of
10“* cm before it has appreciable surface
cner^ Smee the reality of mereased solu-
bility IS evident only m the colloidal range
or less than 0 1 rmcron, for practical pur-
poses solubihty remains unchMged wiUi a
change m particle size
A change of color with a change in par-
ticle size may be seen by the pharmacist
Red mercunc oxide becomes jtUcw when
triturated to a finer state
The particles of a powdered substance
may appear uniform to the naked c)c, jet
there is a wide \anation m the size of the
particles Most of the particles will fall
wilhm a narrow range about the average par-
ticle size, but there will be some much
smaller and some much larger. The per cent
frequencies of the various particles plotted
against the nwan of a group size forms a
“size freijuenty curve ” An average of the
particle size would not mdicate if the par-
ticles were adequately reduced, for there
could be an equal number of very large par-
ticles and very small particles which would
produce the desired average size, however,
the subdivision would not be acceptable By
complex and vaned means, pharmaceutical
mdustry determines size frequency distribu-
tions whenever essential to the production of
an elegant product
The dispensing pharmacist cannot cany
out elaborate measurements, but, as a good
procedure, he can pass all powders through a
sieve to make sure that all macroparticles
have been pulverized and to establish the
upper limits of particle size m the presenp-
tlOQ.
Mechanical subdivision is accomplished in-
dustrially by attrition, hammer or high speed
mills Solid drugs to be used for insufflation,
parenteral or ophthalmic use must be of size
ranging from 1 to 5 microns At times com-
imnution is earned out at low temperatures
to facilitate fracture and passage of clastic
solids such as proteins and mcUiylcellulose
Very small particle size has been attamed ex-
penmcntally by appbcations of freeze dry-
ing. spray drying, ultrasonics and impmge-
ment procedures Since specialized and ex-
pensive equipment is not available to the
pr^Ucing pharmacist, he commonly reduces
particle size by inturatmg a substance m a
mortar with a pestle and/or fay passmg the
substance through a sieve
In the process of tnturation, the pestle is
given a circular motion beginning on the drug
and extendmg lo larger circles until the side
of the mortar is touched The pestle should
be held m the palm so that the four fingers
and the thumb are wrapped about the handle
allowing the application of downward pres-
sure The powder should be scraped fre-
quently from the sides of the mortar with a
spatula. The time required to pulverize a
crystal depends on the mdividual chemical,
however, a minimum of S minutes of tntura-
tion should be employed by the compounding
pharmacist
Porcelain and Wedgwood mortars are
usually found m the pharmacy The pestle
should fit the mortar so that it permits
fnaatmum contact between the surfaces of the
nmitar and the pestle. The efficiency in tnt-
Powders 97
uration depends on the area of contact be-
tween the grinding surfaces as well as on the
pressure applied A rounded pestle m a fiat-
surfaced mortar wastes energy and does not
reduce particle size effectively Glass jnoitais
and pestles are not used for tnturation be-
cause of their smooth surfaces A glass mor-
tar IS used for dissolvmg substances, since it
IS easy to know when solution has been com-
pleted A glass mortar is used m mixing
chemicals, such as lodme and dyes, which
would Siam a porcelam mortar
After a solid has been reduced m size from
the ongmal granule or crystal, it may be
brushed through a sieve to further reduce
particle size or to make certam the proper
degree of subdivision has been obtained The
fineness of pharmaceutical powders is ex-
pressed by the C/ S' P m terms of a precise
range It is interesting to note that the classi-
fication of powder by fineness is different for
chemical and for vegetable and animal drugs
All dosage forms must be uniform to
ensure that the proper dose of medication is
given to the patient Blendmg of the vanous
ingredients is most readily accomplished
when each ingredient is m powderea form
before mixing V-blenders, double conical
and ribbon blenders are used m pharma-
ceutical industry to blend tons of ^wders
The dispensing pharmacist utilizes mortar
and pesUe and sieves to mix a prescription
Ultimately
Alter cacb mgredienl has been pulverized
and then weighed, the drug colled for m the
smallest amount is placed m a mortar and
an equal volume of the drug next in quantity
IS added. The two drugs are triturated until
intimately mixed Then, twice as much of
the third mgredient, again the drug next m
quantity, is added and triturated This is
repeated until all drugs have been mixed
This method is known as mixing by geomet-
nc dilution Although the use of geometric
dilution IS essential when a prescnpuon con-
tains a small amount of a potent drug, geo-
metric dduuon may well be used m aB
blending procedures
POWDERS
Powders are mixtures of drugs and chemi-
cals m a dry, fine state of subdivision
Powders are compounded as bulk powders
Fio 37 Serum levels m humans after
one 3 Gm dose of sulfadiazme Micro-
ciystahme sulfadiazine with the smaller
particle size produces a higher serum
level (Reinhold, 3 G, Phillips, F J,
and Flippin, M F Am J Afed Sci
2J0 141. 1945)
and as divided powders (chartulae) They
are used mleroally or externally There are
powders for pf eparing douche s, du sting and
dental powders, and there are msufSations
K) De mown into body cavities
Powders have certain inherent advantages
The small particle size of powders permits
greater and more rapid dispersion of drugs
than do drugs given m compacted form
Capsules and tablets containing very soluble
drugs, such as chloral hydrate, bromides and
iodides, often irritate the gastromtestmal
Had locally Imlatioa and nausea are caused
by the high concentration of drug m contact
with a small portion of the stomach mucosa
The more rapid diffusion of powders lessens
local irritation
Powders give the physician free choice of
drugs, dose and bulk While many dosage
forms are prefabneated, it would be impos-
sible to have all combmations and strengths
of drug m ready-made dosage forms Ex-
temporaneously prepared powders allow the
phyacian to prescribe any combination of
drugs in any dosage best for the mdividual
patient
Powders permit the admmistrauon of a
large bulk of mcdicmals which would be
prohibitive m size for tablets or capsules
Children and some adults have diificul^ m
swallowing a tablet or a capsule. For such
persons, the powder form may be used to ad-
vantage. Powders are administered orally by
98 Solid Dosage Forms
being siirrcd m part of a glass of u’ater and
swallowed immediately Some persons prefer
to place the powder on the tongue and follow
wi^ a drink of water Taste of the medt*
erne may be improved by mumg the powder
With fruit juice or honey
Powders are not the dosage form of choice
for lU tastmg drugs Drugs which detenorate
readily on exposure to the atmosphere should
not be dispensed as powders wi^ their large
surface area but m a dosage form protected
from the air Ferrous iron salts arc easily
oxidixed and should be dispensed as a coated
tablet
hbdicinal agents administered as solids
must be reduced to powders and thoroughly
mixed with the other mgredients to ensure
uniformity, elunmate grittmess and prepare
an elegant dosage form
Mixmg of coarse and fine particles results
m stratification The coarse particles collect
near the top and the fine particles slip
through the void spaces and collect at the
bottom For this reason, all drugs and cbem*
leals should be reduced to approximately
the same size before wetghmg and mixiog
Even with such precautions, the particles of
the greatest density tend to settle
In the pharmacy powders are most effi-
ciently mixed with mortar and pestle Gentle
trituration produces a light, dufTy powder
Heavy and prolonged tnturation reduces
granules and crystals to a fine powder or
changes a bulky powder to a more compact
one Heavy trituration causes undesirable
cakmg of resinous vegetable powders Rou-
tine siftmg IS excellent to ensure the proper
mixmg and reduction of particle size
When a prescription contains a potent
drug. It IS especially important that a uniform
powder be prepared
Belladonna extract
0^
Phenobarbital
04
Bismuth submtrate
24 0
Kaolm
450
Peppermint od
012
Sig 3 i a.c untd diarrhea has subsided
The belladonna extract, the pbcnobarbital
ind the peppermint oil arc triturated in a
>orcclam mortar until the mixture is homo-
’cncous One, 2, 4 and 8 Gm of bismuth
lubnitrate ore added m sequence with trit-
uration after each addition The remamder
of the bismuth subnitrate and 10 Gm of
kaolin are added and triturated until the mix-
ture is homogeneous On the addition of and
tnturaUon with the remainder of the kaolin,
a uniform powder is obtamed
2. I)
Hard soap 50
Precipitated calcium carbonate 935
Sacchann sodium 2
Peppermint oil 4
Cinnamon oil 2
Methyl saLcylatc 8
Sig N F Tooth Powder
Tbe sacebarm sodium, the oils and the
methyl salicylate are blended with about one
half of the precipitated calcium carbonate
The soap is mixed with the remamder of the
precipitated calcium carbonate The two
powders are mixed thoroughly and passed
through a fine sieve
No mixing procedure is universal Each
prescription must be considered as an mdi-
vidual challenge The method and the order
of mixing IS determuicd by the chemical and
the physical properties of the ingredients and
the intent of the physician
Bulk Powders
Bulk powders arc restricted to those
powders that are nonpotent and can be meas-
ured safely in a spoon by the patient Ant-
acids, laxatives or powders for the prepara
Uon of douches fall in this category
The usual containers for bulk powders arc
pasteboard boxes os wide ssvouth, screw-cap
glass jars The opening should be large
enough for convenient use of a spoon Bottles
are preferred m order to protect the prescrip-
tion from moisture and to retard the loss of
volatile components Powders for external
use should be dispensed with External Use
labels
3 »
Bismuth subcarbooate
Calcium carbonate
Light magacsium oxiJc, aa 30
Peppermint od 01
Sodium bicarbonate q s 180
M fL powder
Sig. Take as directed (Alkaline Powder)
Powders
99
4 I>
Magnesium carbonate 12
Bismuth subcarbonate 3
Calcium carbonate 9
Sodium bicarbonate 30
Taka Diastase 2
Sig 3 1 in HoO t I d
Dusting Powders
A single therapeutic agent may be a
medicated dustmg powder, but, more often,
a base is used as a means to apply a thera-
peutic agent and mamtam it in contact with
the skm Alu min um stearate, kaolm, mag-
nesium stearate, zmc oxide and zmc stearate
impart adhesiveness to a powder Zmc
stearate, starch and talc impart an easy flow
to powders so that they spread uniformly
Dusting powders are applied to loter-
tngmous areas as a covenng which protects
the skm from the chaflng of fnction and
moisture Vehicles such as bentomte, kaolin,
kieselgubr, magnesium carbonate and starch
absorb secretions with a resultant drying
action that relieves congestion and imparts a
coolmg effect The cooling effect is due to
the greatly mcreascd surface for evaporation
and radiation of heat
Dusting powders possess the character-
istics of all properly prepared powders Dust-
ing powders are generally for dermatologic
use, but they are sometimes applied to
wounds and mucous membrunes Since dust-
mg powders are applied to traumatic areas,
they must be gnt free All extemporaneous
dusting powders should be passed through
a 100 mesh sieve Dusting powders are dis-
pensed in sifter top cans or boxes with ap-
propnate directions and auxiliary labels
5 B
Done acid 6
Starch 10
Salicylic acid 2
Talc 78
Sig Apply to feet momiDg and night
The salicylic acid is tnturated to a fine
powder m a porcelain mortar The correct
weight of saliglic acid is tnturated with the
bone acid until the mixture is homogeneous
ISie starch and approximately one third of
die talc are added and tnturated. The re-
mamder of the talc is added and, after tnt-
uration, the blend is passed through a 100-
mesh sieve The foot powder is dispensed m
a sifter-top can
6 B
Paraformolin 3
Talc 60
S>g Apply to feet fa s
7 B
Acelaisooe 4
Kaolin 14
Sodium bicarbonate 14
M Dusting Powder
Sig Spnhklc on affected area
8 B
Tannic acid 10
Bismuth tnbromphenale 10
Powdered boric and 30
Sig Use as du-ected
9 B
Bone and
Sulfathiazole, aa 60
Sig Use as a dusting powder
10 B
2Unc oxide 2
Calamine 30
Starch 1 3
M Dusting Powder
Sig Apply to feet b s
n B
Talc
Starch, aa 30
Lavender oil q s
Sig Use on moist areas
12 B
DDT Powder 105&
Talc, q s 120
Sig Apply locally b i d
13 B
Menthol 0 2
Camphor 0.5
Zinc oxide 5 0
Talc
Starch, aa q s. 60
Sig Apply to affected areas p r o.
100 Solid Dosoge Forms
14 5
Menthol 025
Th}TOoI 0 25
Monobasic sodium phosphate 50
Magnesium carbonate 5 0
Talc, q s 100
Sig Apply as foot powder
Douche Powders
In community pharmacy douches are
limited to aqueous solutions for imgauon of
the vaginal tract In general, the pH ranges
from 3 S to 5 Douclie solutions for the
vagma are introduced by means of a suitable
rubber syringe with a specially designed
nozzle Frequently, the physician presenbes
an mdividuid formula as a powder such that
one teaspoonful dissolved by the patient m
a specified volume of water provides the de-
sired concentration of drugs
Aromatics such as methyl salicylate,
peppermint oil thymol, menthol and cuca
lyptol arc often present in douche powders
for their fragrance, freshness and possible
antiseptic action Dcodonzauon is effected
by peroxides and perborates Alums, tannic
acid, zinc sulfate and zme phenosulfonate
arc used as astringents
15 n
Powdered alum
Zinc oxide aa 30
Oil of peppermint I
Sig Use 5 1 in 1 qt HjO as a douche
16 It
Lead acetate
Powdered borax aa 60
Sig Alkaline Douche use as directed
17 It
Citnc acid 10
Lactose 20
Zinc sulfate 10
Ammonia alum 10
Dried magnesium sulfate 10
Sig Use as douche ut diet
18 It
Aluminum acetate
Bone acid aa 30
Sig. One tablcspoonful m 1 qt H,0
Use as douche q PJ4.
19 It
Bone acid powder 15
Tannic acid 15
Peppermint oil 0 1
Sig 5 1 in 1 qt HjO as a douche
Insufflations
Occasionally, finely divided powders are
mtroduced mto cavities such as tooth sockets,
cats, nose, vagina and the throat The
powder is placed m the chamber of an in-
sufflator, and, when the bulb is pressed, the
air current carries the fine particles through
the nozzle to the area for which the medica-
tion IS intended
Disadvantages of the insufflator are the
difficulty of obtaining a umform dosage and
the tendency of the particles to stick to each
other and the walls of the insufflator because
of electrostatic attraction The newer aerosols
have overcome these difficulties and have
largely replaced the insufflator (sec Chap 8)
20 Ti
Tneofuron Vaginal Powder 15
Sig ut diet
21 I>
Vioform Insufflate 30
Sig Cleanse before insufflation
22 n
Floraquin Powder 30
Sig. Use as insufflation b i d
23 «
Norisodnne cartridges 10%
Dispense Aerohalcr and 12 caitndgcs
Sig Inhale at start of asthmatic attack
24 »
PcniciIJm Inhaler with 3 cartridges
Sig Inhale orally as directed
Divided Powders
The procedure for mixing the mgredients
ID the usual prescription for divided powders
differs m no manner from that followed, and
previously desenbed, whenever dry sub-
stances arc to be mixed by the pbannacist
Bncily, all drugs arc reduced to a fine stale
Powders 10]
of subdivision before weighing The weighed
powders are blended by gcometnc dilution or
by mixing m ascending order of amount
The reason for dividmg the prescnption
mto mdividual doses is to present the patient
with an accurate dose, therefore, the powder
to be dispensed in each paper is weighed
separately Because of vanation m weights
of powder papers, a pair of counterbalanced
wet^ung papers are used mid each weighed
portion of the powder is transferred to the
paper in which it is to be wrapped
Loss of matenal during compounding may
make the last powder deficient m weight To
compensate for the loss of matenal, the in-
gredients for one powder more than the
number presenbed may be prepared if the
drugs are neither expensive nor narcotic
drugs A meticulous pharmacist will not find
this procedure necessary Generally ± 5 per
cent has been accepted as a reasonable error
permissible m compounded presenpuons
There are three types of powder papers
marketed. Vegetable parchment and glasstne
are relatively impermeable and water repel-
lent They are used for volatile and hygro-
scopic substances Lightweight bond paper is
commonly used although it is not moisture-
proof
Hygroscopic and volatile drugs should be
double wrapped with a paraffin and a bond
paper A pharmacist may have his name
pruned on the bond paper so it appears on
the top of the paper after the paper is folded
Colored papers, such as used in Seidhtz
powders, are used to distmguish powders
Colored papers are not readily available and
often must be cut by the pharmacist
Powder papers arc available m a number
of sizes designated by numbers, but, un-
fortunately, there is no standardized number-
ing system The correct size of paper de-
pends on the amount of powder to be
dispensed and the size of the powder box.
The most popular sizes are 2H x 3H inches,
3 X 4Vi inches, 3% x 5 mebes, and 4% x 6
inches
With a little practice the traditional way
of folding powders provides a neat dosage
form
1 Fold over approximately Vi mch of the
long edge of the paper This fold will be the
top of the fimshed powder paper Several
papers should be folded at once to save time
and to obtain a uniform fold
2 With the folds distaL lay the powder
papers side by side so they overlap shghtly
3 Place the weighed powder m the center
of each paper
4 Bring the lower edge up and fit it mto
the top fold (Care should be taken to avoid
powder in. the fold or beyond it )
5 Pull the top fold toward you until it
divides the remamder of the paper approxi-
mately m half
6 Pick up the folded paper with the
thumb and index finger of each hand and fold
the ends over a powder box so that the
fimshed paper will just fit into the box The
ends of the paper should be folded uni-
formly Press the end folds fiinnly with a
spatula to produce sharp creases The spatula
should not be passed over the full length of
the folded paper as this tends to cause some
powdered matenal to cake and it rums the
appearance of the papers by fiatteniog the
roUed edges
Divided powders are dispensed in binged
cover cardl^aid boxes with the label pasted
inside the cover The most common practice
IS to face all powder papers m the same direc-
tion with the top fold uppermost A second
method is to alternate the powders by plac-
ing half of them with the top folds upward
and half with the top folds ffijwnward This
method does not result m as neat an appear-
ance but n permits the fitting of more divided
powders mto a box
The fainged-cover box presents a better
appearance than the outmoded telescope
powder box With the hinged cover box, the
label is an mtegral part of the prescription,
and the hinged-cover box eliminates the pos-
sibility of the accidental interchange with the
lid from another box
The shouldered box is made so that the
folded powders project sli^tly above the
edges of the base without being crushed when
the cover is closed By so projecting, a
powder may be easily removed from the box
Cellophane or plastic envelopes may be
used instead of powder papers for enclosing
the mdividual dose Cellophane envelopes,
which are made of seamed cellophane tub-
t02 Solid Dosage Forms
mg, have a closed and an open end The
correct weight of medicament is placed into
the cellophane envelope using the weighmg
paper as a funnel and taking care that no
po^vder collects at the opening of the en-
velope As the envelopes are fiUed they are
set upnght The open end of the filled en-
velop^ IS folded over approximately inch
and IS creased sharply The folded envelope
IS laid on a pill tile and it is sealed by passmg
a heated spatula over the creased end Since
the envelopes are too wide to be placed on
edge in an ordmary powder box, they are
dispensed by stacking them one on top of
another in the box
Packaging in cellophane envelopes takes
less tunc than traditional powder folding
and makes differences in skill between phar-
macists less apparent Dispensing hygroscopic
drugs m cellophane envelopes protects them
from atmospheric moisture
25 Q
Potassium acetate 1 0
M Ft Chart tales No XV
Sig Ooe powder t i d
Potassium acetate is a deLquescent sub-
stance It 1 $ usually recommended that po-
tassium acetate be dispensed in a liquid form
such as an elixir If the physician insists on a
solid dosage form, the dried potassium ace-
tate may be sealed m cellophane envelopes
The powder will remain dry for two weeks
26 n
Sodium sulfocyanate 0 3
Make 30 powders
Sig One three limes daily
Sodium sulfocyanate is hygroscopic and it
IS normally administered as an elixir If the
dried sodium sulfocyanate is sealed m cello-
phane envelopes, the powder remains dry
for several months
27 i>
Acctopbcnetidine 4 0
Acid acetylsalicylic 7.5
M ft chart #24
Sig Ooe q 4 hr in milk
28 I)
Acctanilid 0 10
Caffeine citrate 0 03
Sodium bicarbonate 0 20
D T D #12
Sig Headache powders
29 B
Extract of belladonna 0 02
Bismuth subcarbonate 0 60
Sodium bicarbonate 0 30
Tales Chart # I Dispense XXIV
Sig One p r n
30 Ti
Bismuth subcarbonate 0 30
Bismuth subgallate 0 30
Powdered opium 0 06
Make powders # 30
Sig One powder as directed
31 I>
Menthol 04
Salicylie acid 2
Sodium chlonde 60
Zme sulfate 6S
Alum 65
Bone acid q s 500
Ft Cha« No XV
Sig Ut diet.
GRANULES
Granulated medication consists of small
irrcgiflar pmhcles.rangmg from 4 mesh-to
10 mTsh size Granules are measured by a
teaspoon, and, as the patient does the mcas-
unng, granules seldom arc used for potent
medicaments Granules may be dietary sup-
pliments such as Somagen or Delcose Gran-
ules Pasoia Calcium Granulate and Aucro-
myem Spetsoids arc examples of medianal
granules to be taken by the spoonful Some
products such as Panalba KM and SugraciUin
Flavored Granules exist as granules which
are to be suspended m water by the phar-
macist before the prescription is dispensed to
the patient
Effervescent granulations arc mixtures of
medicmal agents with citnc acid, tartanc
acid or sodium biphosphato and a bicarbon-
ate They are dissolved in water and taken
imme diately after cffcrvcsccncc subsides
The carbonated solution is a pleasant vehicle
for bitter and saline salts such as magnesium
Capsules 103
Table 13 Specialty Names of Solids in Powdered Form
S?EC1ALTV
Company
Dtsciup-noN
Duchette
Purdue Fredenc
Individual packette of douche powder
Niphanoid
Wintbrop
Instantly soluble dry powder
Spersoid
Lederle
Soluble or dispersible powder
Sterap
UUy
Stenle powder in envelope for topical use
Stenlope
Abbott
Sterile powder in envelope for topical use
sulfate Observation of the effervescence may
be of some ps>chological benefit to the pa-
tient
The evolution of carbon dioxide occurs
very rapidly when the granules are added to
water If powders were added, the violent
effervescence would spill the solution from
the contamer The granules are made to re-
tard solution and effervescence With the
larger sized granule, effervescence is slower
and less violent The rapidity of soludon also
depends on the temperature of the water
The slow reaction m cold water results tn a
more complete caibonauon
The two methods for the preparation of
effervescent granulations are die fusion
method and the wet method In the fusion
method, the blended powders are moistened
by heating in an oven or over a water bath
The wet method consists of moistemng the
mixed powders with some nonsolvent moist-
ening agent In both methods, (he moistened
mass is passed through a sieve and the gran-
ules are dried at low temperatures before
packagmg For detailed process and formu-
lations the reader may consult <4mencan
Pharmacy *
n It
Magnesium sulfate 50
Sodium bicarbonate 40
Tartanc acid 21
Citnc acid 14
Svg One tablespoonful in water
The unefiloresced crystals of citnc acid
are powdered and mixed intimately with the
magnesium sulfate and the dry, powdered
sodium bicarbonate and tartanc acid The
mixed powders are placed on a plate of gloss
or m a suitable dish m an oven previously
* Sprowls, J B Amencan Pbanaacy. 5tb e<L,
Philadelphia, LippmcoU, 1960
heated to approximately lOO^C The mix-
ture IS carefully blended and, when it be-
comes moist. It 15 rapidly rubbed through a
6 me^ sieve The granules are immediately
dried at SO^C
The pharmacist rarely has occasion to
prepare effervescent granules, but he does
dispense specialty products such as Citro-
carbonaie, Bromo Seltzer and Sal Hepatica
Granules are dispensed in wide mouth
bottles which permit the entrance of a spoon
Effervescent granules must be packaged m
a tight container which excludes air and
moisture
33
Citrocarbooate 240
Sig Tw'o teaspoonfuls in glass of water
P c
34 B
Bassoran granules 200
5/g Oae or t»o tesspoaatuh wtdr s
large glassful of water b t d.
35 B
Senokot 60
Sig Tablespoon h s for normal bowel
function
3d O
Siblm 1 lb
Sig Two teaspoonfuls m 8 oz water
h s
37 B
Bronuonyl with barbital 60
Sig Use as directed.
CAPSULES
<^^cs aw gela^ jhcUs to bchllcd with
an iHdmduaI~dose of powdered and mixed
104 Solid Dosage Forms
mgre.dients of^a presc npUon Capsules can
$0 filled with dry materia ls, semisolids and
Iiguids that are nonsolvcnts of gelatin
Capsules are so familiar a dosage to the
physician that it may not occur to him that
they are novel to some laymen, yet, nearly
every pharmacist of long expencnce has had
empty capsules returned to him for refill It
is neither wise nor necessary for a pharma-
cist to volunteer advice on administration of
every dosage form, but, if he has reason to
believe that the customer does not understand
the intention of the physician, it is his du^
tactfully and moSensively to make the cus-
tomer understand Few persons have diffi-
culty m swallowmg a capsule if the capsule
IS placed on the tongue and swallowed with
a dnnlc of water
On occasion, capsules may be adminis-
tered rectally or vagmally Wien so used,
they should be dipped in warm water to
facilitate insertion The physician may desire
the contents of a capsule to be dissolved m
water to make a solution
An important function of capsules is to
elunmate the taste and the odor of drugs by
enclosing the ingredients in an almost taste
less shell which will release the mcdicauon
in the stomach after 10 to 15 minutes
The flexibility from the viewpoint of the
presenber is restricted only by the bulk of
the medication Even this disadvantage may
be overcome easily by adnumstermg sevend
capsules when the bulk prescribed is too great
to fill a conveniently swallowed capsule
CapsuJcs-caiuipl be i^ed with_substanccs
that react with or disso^Tvc gelatin Highly
soluble drugs admmistercd in capsules form
concentrated solutions that irritate the stem
ach mucosa
r L Extemporaneous Capsules
Hard gelabn capsules arc thm shells of
gclaUn ^ch consists of a base and a shorter
Mp^hich fits firmly over the base of the
capsule For human consumption 8 sizes are
available The variation m densities of drugs
and the wide combinations of drugs used in
irescriptions make it impossible to state the
apacity of each size in other than approxi-
aalc terms The manufacturer attempts to
lo this by tables printed on the capsule box
Vs an mitial guide for the student, the ca-
pacit^s of capsules m terms of aspum are
given below
000 — 1,000 mg
00 — 600 mg
0 — 500 mg
1 — 300 mg
2 — 250 mg
3 — 200 mg
4— 125 mg
5— • 60 mg
Three sizes of veterinary capsules are avail-
able They arc Nos 10, II and 12 Their
approximate capacities are 30, 15 and 7 5
Gm , respectively
In addit on to the common colorless cap-
sule, there are a variety of colored capsules
available Ordmarily only the pink and the
colorless capsule are available to the com-
munity pharmacist unless a special order is
placed with a capsule manufacturer
The pink capsules arc used to diflcrcotiatc
between two capsule ptescnptions for the
same person Colored capsules arc used to
encapsulate ingredients that uould appear
unattractive in a colorkss capsule The color
and the size of the capsule used should be
noted on the prescription to assist in com-
pounding refills
Ca p 5ulcs-ar e_stable und e r ordinary condi
tiQOS^^t they absorb ., rnoisture _an d soften
under high humidity A dr^^^here may
cause t hem to become Britifc and crack when
being filled^ In the phaimacy-iLis-advisable
to store the empty capsules in glass.cootamf
ers in whi ch th ey will be protected fr om du st
and extrem es of hum idity
Solids for use m capsules arc prepared m
(he manner presented in the discussion of
powders The ingredients arc reduced by
tnturation to about the same particle size and
then mixed by geometric dilution.
In sclecUng the proper size of capsule it
may be necessary to weigh one dose and to
ascertain by trial the proper size Since many
persons find it_difficu lt to sw allQNYjarge cap-
sules, t he pha rmacist select s the sm allest cap-
sule dim wll conveniently hoId_the pre-
scribed dose The finished ca psule s houl d be
fi iledT cLthat spaces visible wthin
the capsule When the size has been selected,
the rcguircd number of capsules should be
removed from the container, for their re-
moval smgly dunng the fiJlmg process might
Capsules 105
Fio. 38 A band-operated capsule-bihog machine with a capacity of 24 capsules. (Universal
Model Chemi Pbann, 90 W. Broadway, New York, N. Y )
result in the contatumatioa of the remaining
capsules.
In filling capsules, as in all pharmaceutical
operations, accuracy and cleanliness must be
kept jn mind. Each capsules is weighed sepa-
rately because a capsule is to provide an
accurate dose otmedic^Uon
The powder to be encapsulated is placed
on a paper and pressed down with a spatula
until the depth is approximately one third
the length of the capsule body. The empty
capsule base Is held between the thumb and
the index finger and is repeatedly pressed
vertically into the powder until filled. The cap
is fitted over the base and the filled capsule
is weighed usmg an empty capsule oi the
same size as the tare. An empty capsule may
be used as a tare because the empty capsule
weighs little compared with the filled capsule;
thus only a smaU error is introduced due to
variation in weight of the capsule. If the
weight is not accurate, it is adjusted by again
pressing more powder into the base or by
removing a portion of the contents. CerUun
powders pack so poorly that the base must be
held horizontally and the powder pushed into
it by a spatula.
The attraction, of gelatin for rnoisture re-
qmres the pharmacist to observe care~in
handling a capsule A trace of moisture on
the capsule causes a sticky surface to which
dry material adheres. The best method of
pr otect ing the capsuJeJroni moisture Md fin-
ger prints, IS _tOL-wear- finger cots or. rubber
glovcSt.,.
Before compoundmg in the prescription
area, a pharmacist should wash his hands.
Clean hands are especially important when
the dosage form is manu^ly touched. With
open prescription departments, the patron is
able to observe the compounding of his pre-
senpuon. It enhances ^e public image of
the pharmacist when the patient sees the
pharmacist washing his hands, wearing finger
cots and compounding under sanitary con-
ditions.
Another method by which capsules may
be kept free from moisture dunng compound-
ing h to wash the hands thoroughly, dry
them and keep the fingers dry by friction
t06 Solid Dosage Forms
against a towel before each capsule is ban*
died. The towel should be stnpped through
the clenched hngers until a clearly perc^ti-
ble beat is felt
A third method is to use the base of one
capsule as a holder for other bases during the
filling procedure This minimaes contact of
the &gers With the capsules
Regardless of how careful the filling opera-
tion has been, some traces of material be
found on the outside of the filled capsule
This may be removed by roUmg the capsule
between the folds of a cloth or by shaking
them m a cloth which has been gathered mto
the form of a bag
A few hand operated capsule filling ma-
chines have been marketed, one is shown m
Figure 38 If a large number of capsules are
to be made, such a machme saves a con-
siderable amount of time
Occasional prescnptions are received for
Viscid or scmisohd substances or a combina-
tion of dry and liquid substances to be en
capsulated Usually a plastic mass is tonned
and rolled mto a cylmder which is cut mto
the proper number of segments The segments
should be sUghdy longer than the capsule so
that the ends of the capsule are filled
Gelatin is not soluble m alcohol, fixed oJ s
and volatile oil s Ttiese liquHs may be*a t<.
Sensed m h^ gelaSb ca ps^es empty
capSUlcTtases arc supporGd’ by a box m
which boles have been punched. A calibrated
dropper or pipct is used to deliver the pre-
scribed volume mto each capsule base Car e
liquid touchw the edge of the capsule, since
ils'^rescnce will interfere with propezjcal-
1 ^ As an added precaution to ensure seal-
ing, the capsule chosen should be of such a
size that the liquid does not quite fill the base
In fillmg capsules with a liquid bavmg a
disagreeable odor or taste, particular care
must be taken to make certain none of the
liquid remains on the outside of the capsule
If the capsules arc contaminated m the fiUmg
/process, they should be washed with alcohol
before being dispensed
When all the bases have been filled, each
capsule is jealed by moistenins the low er
por tion of th e msTde of the cap^wi tli' water,
fitung'ifbverthe'basc, and giving U a half
turn. A small applicator or a earners hair
^sh di pped in warm water provides a co n-
veme ^way of moisfe ning the caps, cotton
or ^ter'paper~sKouid no t be used, as^ffi ey
t end to le ave li nt on~tEg*gapsTil g~'ARerthe
c^sul es h~a^ ~b'een sealed, they should ^e
placed on a^ heet-o f- paper rwhere they are
allowed to remain fo r an hou r before they
are dispensed ThiTls done to detect poor
seals an dlealM ge
Ca ^es are dispense d m pjas^Vr ^ass
vials are more pbrlablTanlprotect the
capsule^^bett er than pap er boxesTT the vial
is of clear-^ii 5 j)r pJaslicTlhTtabermay be
placed inside the contamer, thnS preventing
It fronTbecomlng soiled A pledgefoTcotton
js p]aced~oirtbtrtop~i>f tbs capstdsn^eep
them from rattlmg — '
38 I>
Acelylsalicylic acid
50
Phecacetm
30
Caffeme
10
Codeine phosphate
02
M cl Ft Caps XX
Sig One q 3 hr
39 B
Cenum oxalate
02
Phenobarbital
0 015
Pepsm scales
04
Disp tales #40 capsules
Sig One capsule t i d p c.
40 B
Benzocaine
0 50
Phenobarbital
005
M ft D T D # 12 capsules
Sig One ut diet
41 B
Codeine phosphate
0 03
Cenum oxalate
010
Bismuth subcarbonate
0 20
Ft tales caps No XXX
Sig One capsule Vi hr before meals
42 8
Papaverine hydrochloride 0 06
Aminophyllin 0 10
Sodium phenobarbital 0 IS
Nitroglycerm 0 0003
DTD Caps No 30
Sig. One Q 1. D
Effect of Properties of Drugs on Compounding Technics 107
43 5
Phenobarbital 20
Papaverme hydrochloride 15
Belladonna extract 10
Tales Caps No I-X
Sig One capsule a c and h s
44 B
Qumme sulfate
Calcium lactate q s
Disp as placebo Misce and fill
capsules 3 grs
Dispense #12
Sig One h s p r n for sleep
45 B
Desoxya 2 5 mg
Thyroid pow der 8 0 mg
La^se q s
Give 100
Sig One capsule t i d 30 nun a c
46 B
Nembutal 0 050
Phenergan 0 025
Tales Caps #12
Sig Onet 1 d p r n pain
Elastic Capsules
In dustrially prepared, capsules ^ed wit h
a liquid, a suspension or a powder^Xrej cnown ,
as'cl iStic capg les i^asti^caps ules are manu-
factJlred by a conUnuous operation that forms
and fills the capsules Warm, molten gelatin
is fed by gravity through a spreader into a
metal drum The gelatm is spread on the
rotating drum fonmng uniform nbbons of
gelatm The ribbons of gelatm convene be-
tween rotary dies surmounted by an injection
apparatus The fill is metered under pressure
just as the capsule is formed As the dies
conUnue to rotate, the capsules are sealed
and cut from the ribbons
Fso i9 Typical examples of elastic gela
tm capsules
49 B
Diethylstilbeslrol Perles 5 mg
Give dozen
Sig One t 1 d for 4 days
50 B
Placidyl 500 mg.
Caps No 30
Sig Oneb s
51 B
Dilantin lO oil 01
Dispense 100
^ Sig Oaet i d
52 B
Heptuna Plus 100
Sig Two daily
(
EFFECT OF PROPERTIES OF DRUGS
ON COMPOUNDING TECHNICS
47 B
Somnos OJ
Caps, No 30
Sig One an hour before retiring
48 B
Muluccbnn 100
Sig One with meals
Nearly all substances dispensed m the solid
dosage form are dry and stable under ordi-
nary Gonditions Compounding and dispens
ug problems and incompatibilities arc en
countered less frequently m solid than m
liquid preparations, nevertheless, some pre-
scriptions require special com|X}unding pro-
cemtres and modes of dispensing because of
the properties of the drugs
108 Solid Dosage forms
Table 14 Specialty Names of Capsules
Specialty
Company
Desciuption
Ccheal
Lilly
sealed elastic gelatin capsule
Kapseal
Parke, Davis
banded, hard gelatm capsule
Ophtbalet
McNeil
soft daslic gelatin capsule, elongated at one end, con
taming sufficient quantity of ophthalmic ointment for a
smgle application to the eye
Pearl
gelatin sealed capsule
Perie
gelatin seated capsule
Pulvule
Lilly
dry filled hard gelatm capsule
Radiocap
Abbott
bard gelatm capsule contammg a radioactive substance
Potency op the Drug
Potent drugs that have doses too small to
be weighed on a Class A prcscnption bal-
ance are diluted with an inert powder and an
aliquot amount is used Ordmanly, lactose is
used for this purpose The aliquot method
IS discussed m Chapter 1 In diluting a potent
drug it >s advisable to add the drug to some
of the diluent m a mortar, after which the
remainder of the diluent is added by geo-
metric dilution By this technic, there is little
loss of drug by adhesion to the mortar
Divided powders weighing less than 120
mg arc inconvenient to administer U the
patient spills a small amount of the powder,
the loss IS an appreciable part of the intended
dose and consututes a serious underdose of
drug For this reason lactose is added to
drugs of small doses to increase the bulk of
the contents of divided powders or cellophane
envelopes to a bulk which can be easily
handled by the consumer
S3 It
Neostigmine bromide 0015
Atropine sulfate 0 0004
DTD Charts No XXV
Sig. One L 1 d a. c.
A total of 10 mg of atropine suUatc is re-
quired for 25 powders This is obtained by
weighing 1 00 Gra of a 1 100 trituration of
atropine sulfate with lactose The atropine
sulfate and the neosugmme bromide arc
blended by geometric dilution To mercase
the bulk, 195 mg of lactose is added per
powder so that each powder weighs 250 mg
Potent drugs to be placed m capsules arc
diluted With lactose to a bulk which is con-
veniently manipulated by the compounding
phannacist Some pharmacists find it diili
cult to handle a No S capsule and prefer to
use, by the addition of a diluent. Nos 3, 2
and 1, which arc convenient for both the
patient and the phannacist
54 n
Papavenne bydrochloride gr 14
Pbenobaibital gr
Belladonna estnet gr Vi
Give 24 caps
Sig One or two capsules pro
The total weight of drugs m each capsule
IS 17/24 gr is too small a bulk to be
convementiy handled by the pharmacist and
will not completely fill a capsule If the
pharmacist adds 2 7/24 gr of lactose per
capsule or 55 gr for 24 capsules, each cap-
sule will contaui 3 gr which can readily fill
a No 3 capsule
In some prescriptions, volatile solvents
may be used to obtain an even distribution
of a potent drug
55 n
lodme 0 5
Bone acid q s 30
Sig Josu/natc as directed
The iodine is dissolved m a volatile sol-
vent Alcohol, benzene, chlorofonn and clhcr
arc suitable \olatde solvents The solution
of lodme IS added gradually to tlic poudered
bone acid m a glass mortar with trituration
until thesolventhas evaporated Contact with
metal should be avoided. Due to the vola-
Effecf of Properties of Drugs on Compounding Technics 109
tility of the iodine, the powder should be
packaged m an airtight glass container with
aplastic cap
Incorporation of Liquids
A smaE volume of a liquid may be tntu-
rated with an equal volume of powder, and
the remammg powder added m portions with
tnturation With the exception of flavoring
Oils, the majority of liquids found m ex-
temporaneous prescriptions for solid dosage
forms are tmctures or fluidextracts It is
withm the province of the pharmacist to re-
place, without consultmg the physician, one
of these liquids with an equivalent amount of
the corresponding extract
56
Belladonna tincture 0 6 ml
AcetylsaLcylic acid 300 mg
M Disp Cap tales no x
Sig One capsule as directed
Belladonna tmctuie contains m each 100
ml 0 03 Gm of the alkaloids of belladonna,
belladonna extract contams m each 100 Gro
1 Z Gm of the alkaloids The extract is 40
times the strength of the tincture, and the 6
ml of tmcture prescnbed may be replaced
withO ISGm of the extract
If the extract is not available, the liquid
may be concentrated to a small volume and
lactose added before evaporatuig to dryness
Lactose acts as an absorbent on the surface
of which the residue piecipitates, conse-
quently avoidmg a sticky residue when evapo-
ration is complete
57 n
Hydrastis fluidextract
Bismuth subnjtrate
Sodium bicarbonate, aa 15
M et div m chart, no x
Sig Take 1 powder, mixed with water,
after each meal
The fluidextract must be evaporated, since
the amount of dry material prescribed is too
great to permit the addition of suffiaent men
substance to adsorb the large volume of
liquid The fluidextract is evaporated on a
ualcr bath, at a temperature not exceeding
70®C, to a sjnipy consistency Lactose is
Table 15 Vapor Pressure of Some
Volatile Pharmaceuticals
COMVOUND
Vapor
Pressure
(m ram of
Mercury)
Temperature
(degrees
centigrade)
Acetophenone
0 213
25
Camphor
055
23 4
Iodine
0202
20
Menthol
0 94
28 4
Naphthalene
0 082
25
Paraformaldehyde
10
24
Phenol
1
44 8
Phosphorus white
0025
20
added and the heat continued until a dry
powder is formed This is then intimately
blended with the other mgiedients of the
prescnption
If an extract is not available, a small vol-
ume of a liquid may be adsorbed on the other
ingredients
58 n
Calcium carbonate
Bismuth subcarbooate
Sodium bicarbonate, aa 15
Peppermint spint 8
M etdiv m chart no xxiv
Sig One powder after meals
There is sulScient dry material to adsorb
the peppermint od which remains after the
evaporation of the volatile alcohol
The technic selected depends on the rela-
tive amounts of the liquid present Evapora-
tion should be used as a last resort, smee it
IS usually attended by a sigmficant loss of
matenal
Volatility
Volatility IS the tendency to enter the
vapor phase Volatihty is roughly propor-
tional to the vapor pressure and mvcrsely
proportional to Ae bodmg point To vola-
tilize. a solid must have an appreciable vapor
pressure below its meltmg point
At a given temperature the vapor pressure
of a solid is mdicative of its volatility Only
a few soLds have a high enough vapor pres-
sure to sublime at atmospheric pressure
Volatilization is immeasurably slow if the
110 Solid Dosage Forms
Fio 40 Vapor pressure of water m a
waicr-ashydrous salt system at constant
temperature
vapor pressure of a ci}'stal is low The rate of
volatilizatioa depends not only on vapor pres-
sure but also 00 temperature and pressure
The vapor pressure of some solids that are
volatile m the region of room temperature
are given m Table IS It appears that a sohd
with a vapor pressure exceeding 0 1 mm. of
mercury will vaporize readily
A dosage form contamiag volatile sub-
stances such as camphor, lodme and menthol
should be tightly sealed to miaimize loss by
vaponzatioo.
Bulk powders, capsules and (ablets con-
taining volatile substances arc dispensed m
airtight glass cootaineis Divided powders
should be double wrapped with an itmcr par-
afhn and a bond paper Protection from loss
IS mereased by use of cellophane envelopes
sealed with beat
59 J)
Pbeaacetio
Quinine, aa
0065
Sodium salicylate
010
Powdered capsicum
COOS
Peppermint oil
020
M ftXIIcaps DTD
Sig.. Ut diet for gnppc
60 n
Chlorobutanol 0 2
M etft caps No 12
Sig One capsule hourly for 3*4 doses
61 9
Camphor 0 030
Belladonna extract 0 008
Quimne sulfate 0 060
M etft capsules No 24
Sig One every 2 hours for 4 doses
Industrially formulated capsules and tab-
lets containing volatile substances are often
coated to retard loss of volatile ingredients
62
Rhinitis (Full Strength)
Give 12 (ablets
Sig Two tablets daily
HVD RATION
Crystal hydrates that are stable m the air
between certain limits of humidity are said
to contain water of crystallization
A muture of a saturated solution of a salt
with the solid has a constant vapor pressure
at a given temperature Diagrammatically,
the change of vapor pressure from pure water
to pure salt is shown m Figure 40 for sodium
mtrate
Point N corresponds to pure anhydrous
sodium nitrate with zero vaj^r pressure As
the salt IS dissolved m pure water (W) hav-
ing a vapor pressure of Y, the vapor pressure
of water decreases to X, where the solution
is saturated with sodium nitrate correspond-
ing (oS
P represents the vapor pressure of the
saturated solution, the ratio of vapor pres-
sure of the solution to pure water is 0 74
at TS'C If the relative humidity of the air
IS higher than 0 74 — for example, H — the
sodium mtrate will attract water and form
a saturated solution After all of the sodium
nitrate has dissolved, it will continue to ab-
sorb water until the composition of the solu-
tion (G) has the same relative vapor pressure
as the atmosphere This phenomenon is deli-
quescence and occurs oiily when the humid-
ity of the air is greater than the vapor pres-
sure of the saturated salt solution
If the relative humidity of the air is less
Effect of Properties of Drugs on Compounding Technics 1 1 1
than 0 74, solid sodium mtrate remains un~
changed
Depeodmg on the humidity, a salt hydrate
may remam unchanged, deliquesce or give
o2 water Sodium bromide can exist as the
dihydrate and as the anhydrous salt A satu-
rated solution of sodium bromide has a rela
tive vapor pressure of 0 57 at 25°C It will
deliquesce when the relative humidity of the
air IS greater than 0 57 The dihydrate has
a relative vapor pressure of 0 36 at 25*0
and therefore will give off water when the
relative humidity is less than 0 36 This is
called efflorescence Sodium broimde dOiy
drate is stable only when the relative humid-
ity ranges from 0 36 to 0 57 at25°C
*1110 U S P states that borax effloresces
m dry air The vapor pressure composition
curve shown m Figure 41 provides a more
complete characterization of this substance
A saturated solution of borax has a relative
water vapor pressure of 0 99 at 20 "C , for
all practical purposes deliquescence does not
occur The relative vapor pressure of borax
IS 0 39 at 20°C when it is m equilibnum
with the pentahydrate Thetefore, if borax
IS exposed to air with a relative humidity less
than 0 39, it will effloresce to the pentaby-
drate The pentahydcate is stable only at
relative humidities between 0 39 and 025,
if the relative humidity becomes less than
0 25, the pentahjdrate will effloresce to the
anhydrous salt
^me common ciystallme drugs that liber-
ate their water of crystallization m an at
mosphere of low humidity and become pow
deiy m appearance are atropine sulfate,
scopolamine hydrobromide, terpin hydrate,
zinc sulfate and the sulfate and the phosphate
of codeme
Zinc phenolsulfonate effloresces when ex-
posed to the air If all of the water of hydra-
tion were removed from the zmc phenol-
sulfonate, there would be a loss of 25 per
cent of Its weight Efflorescence may alter to
a practical extent the dosage of a patient
If cmcbonme bisulfate effloresced all of its
water of crystallizatiod, there would be a
loss of IS per cent of its weight Thus, a
pharmacist weighing effloresced cinchonine
bisulfate instead of hydrated cmchoiune bi-
sulfate would be dispeosmg a 15 per cent
greater dose
COMPOSITION
Fio 41 Vapor pressure of water in ;
water-borax system at 20* C
A solid contaming water of crystallization
may lose such water to a greater or less ex-
tent on tnturation as a result of the heat de-
veloped Fuitbennore, any occluded water
held mechanically m the mterior cavities of
a crystal will be released as the crystals are
reduced to smaller particle size
Ugbt tnturation is recommended with so-
dium phosphate, sodium sulfate, alums and
ferrous sulfate The best method to ensure
a dry powder is to use an equivalent amount
of the anhydrous chemical If the anhydrous
chemical is not available, the hydrous form
may be dried before mixmg
63 n
Magnesium sulfate
Sodium sulfate
Sodium potassium tartrate aa 15
Sig Heaping teaspoonful m half a cup
of hot water night and morning
On triturating and mixmg the three salts
a pasty mass is formed A satisfactory pow-
der could be prepared by usmg equivalent
amounts of the a]m}drous form of ffle salts
The prescription should be dispensed m a
tight glass container
64 Q
Sodium sahcylate 6 0
Sodium sulfate 6 0
Sodium bicarbonate 3 0
Potassium bitartrate 6 0
M ft Chart # XX
Sig Take one q i d a. c. & bedtime
112 Solid Dosage Forms
»t» CCMT «t*T(ll
Fio 42 Imbibition of water by potato
starch
Hygroscopicity
Solids exposed to the atmosphere gener-
ally adsorb some water vapor on their sur-
faces This IS called water of hygroscopicity
It increases with an increase in surface area
and humidity The relation between the
amount adsorbed and the water vapor pres-
sure IS given by an adsorption isotherm Ad
sorption IS relatively large at small pressures
and changes rapidly with vapor pressure
change
A polar molecule such as water is strongly
attracted by ions or polar molecules on the
surface of a crystal lattice and held firmly
by dipole ion or dipole-dipolc interaction,
respectively
Colloidal substances such as cellulose,
starch, agar and gelatin adsorb large amounts
of water and retain the appearance of dry
powders Such water is cidied water of im
bibiuon The tvaCcr content vanes with hu-
midity As shown m Figure 42, potato starch
contains 10 per cent of water at a relative
humidity of 0 20 and 21 per cent of water
at a relative humidity of 0 70 Thus, if the
seal IS not airtight, the water content Ganges
with the seasons
Double wrapped divided powders and
sealed cellophane cn\ elopes usually arc suffi-
cient toprotcct hygroscopic substances
65 I)
Sodium bromide
Sodium salicylate, sa 10
Ft chart XXXVI
Sig Oneq 1 d
66
Pbeoobarbital 0 03
Ferrous sulfate 0 30
M ft D T D #12caps
Sig Uno daily
67 «
Phenol
Menthol, aa 0 5
Alum 30
Bone ocid q s 120
Sig 3 1 to 1 qt hot water for douche
An older method of dispensing hygroscopic
powders in a divided powder or a capsule
employs the mcorporalion of an inert sub-
stance that preferentially absorbs moisture
Talc, magnesium oxide, magnesium carbon-
ate and starch have been suggested for this
purpose The divided powder is then double
wrapped usuig an inner paraffin paper
68 U
Feme ammonium citrate 0 5
Ft caps tal dos XX
Sig Onet I d
If the feme ammonium citrate has been
exposed to the air and has absorbed mois-
ture, It Will gum up wbco triturated in the
mortar Dry feme ammomum citrate may
be put into capsules If the capsules are ex-
posed to humid air, moisture is absorbed
wiihm a week If 60 mg of magnesium car-
bonate 25 added per capsule, the capsule will
remom dry after exposure of several weeks to
the atmosphere
The choice of inert ingredient depends on
the presenpUon Magnesium oxide is alka-
line and, m the presence of moisture, will
hydrolyze esters If a dear solution is to be
formed, an insoluble absorbent cannot be
used
69 2 )
Ammonium bromide 0 I
Talcs Chart XII
S/g Use Of directed
Ammonium bromide absorbs moisture
from the air If magnesium oxide were added,
aminontn would be liberated m the presence
of moisture The dry ammonium bromide
may be dispensed m the form of a divided
Effect of Properties of Drugs on Compounding Technics 113
powder if double wrapped papers or cello-
phane envelopes are us^
Deliquescent substances may absorb water
from a capsule shell and cause it to crack
Inert absorbents of moisture will aid m main-
tammg a dry powder, although they are m-
effective if the capsules are dispensed m a
box Capsules containmg dry deliquescent
and hygroscopic drugs dispensed m moisture-
tight vials remain stable for long penods of
time without the addiDon of an mert powder
70 U
Sodium citrate 0 12
Calcium iodide 0 06
Guaiacol carbonate 0 03
Aspinn 0 30
Tales caps No 12
Stg One after each meal
Depression of Melting Point
The meltmg points of certain substances
that are sohds at room temperature are low
ered by contact with certain other substances
to the pomt at which liquefaction occurs
Commonly dispensed drugs exhibitmg this
phenomenon are acetanilid, amioopyrme,
antipynne, betanaphthol, menthol, tnymol,
phenol, chloral hydrate and the salicylates
Any substance that has low mtermolecular
forces as mdicated by low meUmg pomt, soft
crystallme structure or easy sublimation will
probably liquefy when triturated with a
chemical of simdar nature Such compounds
usually contam aldehydic, ketonic or phe
nolle groups
Impunties added to a chemically pure com-
pound will for the most part lower the melt-
ing point of that substance If the melting
pomts of such mixtures arc high, the phe-
nomenon offers DO problem to the pharma
cist. However, many drugs used m medicine
have a low meltmg pomt, and, when they arc
mixed mtimately with other drugs, the low-
ered mixed meltmg pomt becomes less than
room temperature and the mixture liquefies
Considcnng atmosphenc pressure con-
stant, the particular state that a mixture exists
in IS primarily a function of temperature and
composition Smee phannaceuticals are pre-
pared to be stable and to be used at room
temperature, temperature is not a vanable
To the pharmacist the important factor m
PER CENT CAMPHOR
Fio43 Phase diagram for a salol camphor
mixture
detcrmming the physical state of a mixture
IS Its composition
From the phase diagram m Figure 43, the
physical stale of a mixture of camphor and
salol ciui be determmed Pomt A is the melt-
ing point of pure salol Along the Ime AO
pure salol is separating from the mixture
Pomt B represents the meltmg pomt of pure
camphor, and along BO solid camphor is
separating At O both pure salol and pure
camphor exist, this is the eutectic pomt At
room temperature of 25 ®C , this bmary mix-
ture IS a liquid when the camphor makes up
from 15 to 50 per cent of the mixture
71 13
Camphor 120 mg
Salol 300 mg
M ft Powder No 6
Sig Use as directed
114 Solid Dosage Forms
Camphor composes 29 per cent of the pro*
scnptiofl At 25®C the mxxiure will be a
liquid A salol-camphor prcscnption con-
tammg 75 per cent of camphor will be a dry
powder
Unfortunately, phase diagrams are not
available for the multiplicity of combmations
found m prescriptions The physical state de-
pends not only on the proportion of the low
mc]ung point ingredients but also on the rela-
ti\e proportion of the higher melting point
mgredients If a liquid is formed, there may
be a sufficient quantity of higher melting
point material to absorb it effectively With
the almost mhnite combmations possible m
medicines, it is difficult to make an accurate
prediction of the physical state The prac-
ticing pharmacist should recognize probable
offenders and compound them as ffiough a
liquid would form
If the amount of Iiquefymg ingredients is
small compared with the entire prescription,
they may be mixed and the bquids taken up
in the pores and on the surface of other
ingredients
72 l>
Salicylic acid
50
Menthol
20
Camphor
SO
Bono acid
500
Starch
350
Sig Dust as directed
The camphor the menthol and the sah-
cylic acid arc triturated until liquefaction oc-
curs The boric acid is added gradually with
trituration until the liquid is absorbed The
starch IS then added and triturated oatd the
prcscnplLon is homogeneous
If the amount of liquefying substance is
largo and cannot be absorbed, each of the
Iiquefymg drugs is mixed separately with an
mert, high melting pomt protective and then
mixed lightly The inert protective acts as a
mechanical barrier or coat to present con-
tact between the low melting pomt sub-
stances Further, if any liquefaction occurs,
the liquid is absorbed by the large surface
of the protective mgrcdient-
73 n
Chloral hydrate 0,25
AcetyUalicylic acid 025
M ft Caps No XX
Sig Two on retiring
If the acetylsalicyhc acid and the chloral
hydrate are tnluratcd, a hquid is formed
The amount of inert substance required to
absorb the liquid would be too bulky for a
capsule Each drug is mixed with an mert
ateorbent such as kaolin or talc to prevent
the formation of a liquid The chloral hy-
drate IS mixed with 100 mg of kaolm and
the acetylsalicyhc acid is mixed with 100 mg
of kaolin The two mixtures are mixed lightly,
and the dry powder is filled into No 00
capsules
74 J)
Acid acetylsalicylic 7S
Acctophenctidin 4 0
M et ft capsules No 24
Sig Two capsules t i d a c
75 li
Mcnihol 0 065
Phenol 0065
Zme oxide 60
5ig Apply ut diet
76 n
ASA 0 300
Metheoarauie 0 050
Magnesium oxide 0 100
Caffeine 0 075
M caps DTD #XXX
Sig Oaap r a headache
Probably the high melting pomt and a
large specific surface are the primary criteria
of a good mert protective The dUtercnces
observed between various protccuvcs em-
ployed may be largely those of particle size
and coating ability Decreasing the size of an
mert protective by one half will reduce by
one half the weight of the protective needed
to coat the Iiquefymg mgredients
Kaolm, magnesium oxide and magnesium
carbonate arc commonly used as mert ab-
sorbents Magnesium carbonate is generally
the protective of choice as the oxide may
react W7th other ingredients, carbon dioxide
or water to form a hard, insoluble mass
Effect of Properties of Drugs on Compounding Technics 115
To avoid liquefaction of a mixture of lique-
fying substances, an inert, high melting point
substance is generally added to surround or
coat the drugs, thus preventmg them from
coming mto contact with each other The
amount of inert protective may be ration
ahzed by considermg the effect to be only a
mechamcal coatmg of the particles
77 5
Salol
Ammopynne, aa 02
M et fiat caps D T D No 50
Sig. As directed
As the melting points of salol and anuno-
pynne are 43“ and 104“C , respectively, one
would anticipate possible liquefaction As-
suming spherical particles, trituration m a
Wedgwood mortar will reduce the average
particle size of the two drugs to a radius of
100 microns The densities of salol and
ammopyrme are approximately 1 0 and I I,
respectively Because of its high melting
point (2,800“C ) and its large specific sur-
face area^ magnesium oxide is chosen as the
inert protective Magnesium oxide has an
average particle size of 10 microns and a
density of 1 25
1 The area of a single particle of salol is
A, = 4wR2 = 4n.lO-* cm®
2 The area covered or “shadowed ’ by a
smgle particle of magnesium oxide is
A = rR» = Tl0-«cm®
3 The number of particles o! magnesium
oxide required to coat one particle of salol is
A, 4-10^ =400
A ,r 10-«
4 Theweightofasingleparticleofsalolis
Wj = V p =-|-Tr R’ p =
419XlO-«Gin
5 The total number of particles of salol
in the prescription is
6 The number of particles of protective
needed to coat all p^cles of salol is the
number of particles of salol multiplied by
the number of particles required to coat one
particle or
2,4X 10«X400 = 96X 108
7 The weight of a single particle of the
protective ingredient is
W = V p R* p = 4 19 ( 10 - 3)8 1 25 =
52XlO-‘*Gm
8 The total weight of protective required
to coat 10 Gm. of salol is the number of par-
ticles of protective multiplied by the weight
of a smgle particle of the protective or
52xl0-»x96Xl09 = 5Gra
9 Following the same reasonmg, it is
found that 4 54 Gm of magnesium oxide is
required to coat 10 Gm of anunopyrme
10 The total amount of the inert pro-
tective necessary to coat the salol and the
amioopyrioe is 9 5 Gm
Trial and error have demonstrated that if
each of the hquefymg substances is diluted
with an equal amount of inert absorbent, the
result will be a dry powder The above cal-
culation, based only on mechamcal con-
sideration, agrees rather well with the quan-
tity detenmned by yean of experience
Chemical Reactivity
Explosive mixtures usually consist of oxi-
dizmg agents and orgamc compounds The
stronger oxidizing agents used in pharmacy
are potassium cUoiate, potassium perman-
ganate, sodium peroxide and silver nitrate
The common reducing agents involved m
explosions have been charcoal, starch, sugar,
tamuc acid, sulfur and the sulfides
With potentially explosive mixtures, tritu-
ration is to be avoids If the powders are
to be mixed, they should be tnturated sepa-
rately, and then mixed hgbtly with a spatula
or by tumbling the powders As a safety
measure, it seems obvious that potentially
eiqilosive mixtures should not be dispensed.
If the physician insists on such a combina-
tion, It IS advisable, with his consent, to dis-
pense the two ingredients separately
1 16 Solid Dosage Forms
78 n
Potassium chlorate 7 5
Taniuc acid 4 0
Sucrose IS
M et ft chart 12
Sig One p r n gargle in glass of water
79 I>
Sulfathiazole 5
Sodium peroxide 15
Bone acid 80
Sig Dustonvroundt i d
The sodium peroxide wiU oxidize the
sulfathiazole It should be suggested to the
physician that the sodium peroxide be elimi-
nated and a less caustic, nonoxidizing type
of antiseptic be dispensed
Light may provide the energy necessary
for a reaction to occur without a change m
temperature Acetazolamide, bismuth salts,
cyanocobalamme, many dyes, fumagiUm,
mercury and silver salts and many other
drugs are light sensitive Photosensiuve drugs
should be dispensed in amber glass contain-
ers If a suitable amber container is not avail-
able, the dispensing pharmacist should
dispense the prescnption m an opaque con-
tainer and caution tne patron that the medi-
cation should not be exposed to light
Some chemicals and drugs such os lodme
react directly and rapidly with metal Care
should be observed in the choice of utensils
to be used with such drugs Metal spatulas
and metal sieves cannot be used Other chem-
icals, such as phenols, undergo reactions
catalyzed by trace metal irapunties from con-
t&iocrs or metal utsRSiis PlasUccaps arc used
on prescription containers as they arc less re-
active than metal caps
When solid dosage forms arc dry, acids
and bases or bicarbonates may be mixed
without any reaction If the pharmacist wishes
to use this tcchmc, he must begin with dry
chemicals, compound m a relatively dry at-
mosphere and dispense the finished dosage
form m a contamcr that seals out moisture
80 »
Pamis)! 05
Sodium bicarbonate 0^
Mix and dispense 50 powders
Sig One powder
The Pamisyl and the sodium bicarbonate
were mixed and the weighed amount of the
mixture was packaged in paper envelopes
On dispensing, the powders seemed properly
prepared, however, m 3 days the patient re-
turned and compJamed that some of the en-
velopes were not as full as the first ones he
had taken Actually, the powders had been
accurately weighed The ammosalicylic acid
had reacted with the sodium bicarbonate, m
the presence of atmospheric moisture, dmu-
natiug water and carbon dioxide with a loss
in weight It could be suggested that the phy-
sician use lactose, if the sodium bicarbonate
IS used as a diluent, however, if the sodium
bicarbonate is present to form the soluble
sodium ammosalicylate, this would not be
acceptable
81 B
AminophyUine 0 2
Ascorbic acid 0 I
M D T D Caps No XXV
Sig One capsule 1 . 1 d
For several days the capsules appear to be
satisfactory, but within a week the powder
becomes gummy and brown and possesses
an ammoniacal odor In the presence of mois-
ture, the loosely complexed ethylcnediamiac
reacts with the ascorbic acid With the con-
sent of the physician, the aminophylhne and
the ascorbic acid may be dispensed sepa-
rately or an equivalent weight of anliydrous
theophylline may replace the ammophyllme
COMPRESSED TABLETS
A compressed tablet is a unit dosage form
prepared by*cohipfessing.uHdci: several hun-
dred kJograms of pressure per square centi-
meter granulated medicinal substances into
a discoid shape by means of dies A tablet
usually has a thiclmcss less than one half of
Its diameter 5ome_t abIets-ha ve di sunctivc
sha pis and size s as a mea ns of associ ating
their identity with a particular company The
physical charactcnsucs of industrially pre-
pared solid dosage forms are so distmctivc
that the Amcncan Medical Association in
1962 published an IJenuftcasion Gmde for
Solid Dosage Forms This guide enables one
to identify tentatively a tablet, a capsule or
Compressed Tablets 1 U
a suppository by the use of physical char-
acteristics, such as size, shape, color, mark-
mgs and coating The tentative identification
IS then confirmed by chemical analysis
In a recent survey it was found that 47 6
per cent of the prescriptions were for com-
pressed tablets There are several advantages
of compressed tablets that make them the
most popular dosage form The obvious ad-
vantage of compressed tablets is the con-
vemence of transportation for the manufac-
turer, the pharmacist and the patient AH
pharmaceutical dosage forms are accurate
dosage forms, and, usually, the compressed
tablet IS an accurate dosage m which one
tablet represents one dose A tablet may be
scored into halves or quarters, and a uniform
tablet assures practical division by the pa-
tient into one half or one fourth of the total
dose m an intact tablet
Unpleasant tasting drugs are rendered ac-
ceptable by coating the tablets This may be
a sugar coat, a film coat or a press coat The
coating need be designed to protect only dur-
ing the short time in which the tablet is m
contact with the taste buds
The patient geQ « »rill*^ fioda-a^fahlftr-fh e
^ mplest dosaggJ onnJoLielCjdmiiustTation
The intended route of administration deter-
mines the size and the shape of the tablet
The ma ximum size can not exceed the size of
the Body' passage t^ugh which the tablct-is
to be passed or placed An oral tablet for an
eter The bulk of the dose may decide the
size of the tablet When this exceeds 500 mg ,
most manufacturers divide the therapeutic
dose between two tablets, and this becomes
the prescribed number of tablets for a ther-
apeutic dose
The tablet is placed on the tongue and
swallowed by dnnkmg a glass of water Some
to swallow a tablet For su^ p ersons for
c hddren, a tabl eUshouldJirst-be crushetCand
moistened with water The death of a child
In th e larynx has_b geajeRoacd>,
~"The pharmaceutical industry has made it
still easier to administer tablets by develop-
ing the chcwable or the soluble oral tablet
The chcwablc tablet has a base, such as
mannitol, which can be chewed or allowed
to dissolve m the mouth
Tablets provide a broad range of drug re-
lease Tablets can be designed for a rapid
release of a drug, as illustrated by the many
vaneties of fast-actmg acetylsalicyhc acid
denvatives that are marketed Consistent wit h
p hysiologic functio n, sustai ned re lease tablets
provi de-r&l ea'se ofTdrug over a p eno~d of 8
to 12 hou^ mamta mmg an adequate dosage
witlT the Mnvenience of a smgle admmistra-
tion
Our sophisticated society will not accept
unappealing medication A dosage form must
be appealmg to the patient m order to re-
ceive his cooperation m following the dosage
regimen established by his physician Tablets
are made elegant by coating, coloring, flavor-
ing, designing appealmg shapes and sizes and
packaging m attractive containers The at-
tractiveness of tablets and the possibihty that
they be mistaken for candy by children makes
It necessary that tablets, as well as other
medicmals, be kept out of reach of children
Elegant tablets have been made available
to the patient by our pharmaceutical mdustiy
at a reasonable cost, because tableting lends
Itself to mass production methods £at in-
crease production while decrcasmg the cost
of latKir An elaborate distribuuon system
makes readily available to the consumer, at
low cost, tablets m a wide range of strengths
Tablets are not only convement for the
pharmacist to store and package, but tablets
have few serious disadvantages Tablet for-
mation 15 limited by the physical and the
chemical properties of a drug A tablet from
an ethical firm implies that the research and
developmental pharmacist has corrected or
elumnated any problems of stability, incom-
patibility or other formulation problems prior
to marketing the tablet, thus, die community
pharmacist, the physician and the pauent are
not concerned with such problems, except as
(hey may affect therapeutic value
Although compressed tablets arc imprac-
lic^ for die community pharmacist to pre-
pare because of lack of tune, equipment, ade-
quate control and advanced training, the
^lannacist must have knowledge of the
methods of preparation, the factors m their
proper disintegration, the correct storage
Its Solid Dosage Forms
condiUoas, the types of containers to use, the expected to determine analytically the purity
types of tablets available and their particular a:^ the accuracy of manufactured products,
advantages and disadvantages. The |Aar> The pharmacist, acting on faith and the repu-
macist must be able to converse and advise tation of a firm, accepts label claims of pre-
mteliigently about all phases of tablets from fabricated products. The pharmacist therc-
production to administration so that be may fore should buy products from an ethical
be of service to the physician and his patient firm with a good reputation. This is his best
(secChap. 2). assurance that the manufactured product is
A pharmacist dehvers medication to a pure and accurate,
consumer with an unphed warranty that the
punty and the dosage is proper. In extern* Manufacture of Compressed Tablets
poraneous presenpUons, the pharmacist tahlpts are mnniifnctnreH by
exercises great care to make certain each two methods; dry granulation a nd wet gran u-
prescnption is an accurate dosage form. For lation. T o compress a t ablet, t he ingredient s
obvious reasons, the pharmacist carmot be m ust be fr^ flowm g. b inding _and. nnonrifig.
Fio. 44 The Tornado mill may be used for granuIaUng, pulverizing and dispers-
ing. (F. J. Stokes)
Fig 45 Oven designed for efficient drying of granulauons (F J Stokes)
to _the punches and t he die Most
must be formed into granule s Granulation is
the p rocess by w hich fine powders are con-
verted to gr^uies witH' th e above charac ter-
i stics to'assur e uniform fillip and the fonoa'
tion o f an easHv^cted tablet .
It appears that when the active ingredients
are less than 25 per cent of the finish^ tablet,
they may be blended with spray-dned lactose
and compressed directly
WET GRANULATION
Weighing and Mixing the Ingredients.
When a production batch of tablets is to be
manufactured, the master formula card is re-
produced and sent to the chemical and drug
supply department Th ere, the specified
wej^jjf^cach mgredient is wcigbed^and
chewed. The weired material is sent to the
tablet department where each item is care
fully recbccked
M dry mgredieots are in the powdered
120 Solid Dosage Forms
fonn so that t hey will pass through a 60-
mes h sie ve The powders a re blended b y
gcor^tnc_diIution u sing V Slenders or other
suitablcjncchanical mixers
Many of the newer synthetic drugs have a
small dose, and it is necessary to increase the
bulk of the tablet to a practical and work-
able size Common diluents are lactose,
sodium chloride, maimitol, calcium carbon-
ate, calcium sulfate and dicalcmm phosphate
>Vct Granulatmg After the powders are
blended, a Iiqyid granulatiQg.oc.bmdmg solu-
tion is added to form an.adhesive moss which
can be granulated The amount of liquid must
be detemuned empirically for each new for-
mu/atton but it is reproducible from batch
to batch with a production formula The
liquid IS blended thoroughly into the mass
with a nbbon blender or other suitable me-
chamcal mixers When the mass has the
proper consistency, it is forced through_a wet
gr anulator with a 6 m es h to 10 mesh sc reen
'me adhesive matcnals used To bind the
powders togeffiefThto granules are 5 to 10
per cent starch paste, 70 to 85 per cent
sucrose solution, 10 to 20 per cent gelaim
solution, 10 to 20 per cent acaciajmucila^,
25 to 50 per cent gl^ose solution, 5 to 10
per ce nt methsiccllulo se solution, 5 per cent
cthylcellulose solution and polyvmylpyr-
rolidonc Water and alcohol act by means
of their solvent clTect on the ingredients
Uniform distribution and the amount of
the binder are critical InsufEcicnt bmder
leads to poor adhesion, capping and soft
tablets Excessive binder yields a slowly dis-
mtegrating and hard tablet, cxcessne bmder
makes graouJaUcgi e.itremeiy djJBeult
Color may be added to a tablet to convey
a cbaractcnsUc identification, increase pa-
tient acceptance or suggest a flavor Certified
d}cs arc generally distributed throughout the
dry mix or dissolved in the binder solution
A 40 mesh granulation is advisable to avoid
a mottled tablet
In a recently developed mixer, the bmduig
solution may be added slowly as a spray
Some formulations will form granules with
a mini mum of liquid and make it unnecessary
to pass die mixture through a wet granulator
Drjing The wet granulaUon is spread m
a dun layer on trays and dried m an oven
at a controlled teropcnilurc generally not ex-
ttedm g 55 °C
Granulating for Compression. The dried
^nulaiioQ IS ground to a size appropnatc
to the size of the finished tablet For small
tablets such as V4 inch in diameter, a 30-
raesh screen should be used, for tablets up
to % inch a 12 mesh screen should be used
An oscillatmg granulator has an advantage
m that, as soon as a particle is reduced to the
proper size, it falls through the screen away
from the grinding action and is not further
reduced in size Grinding type granulators
and the Fit^atnck comramutor tend to pro-
duce an excess of fine powder
Many tablets are engraved or embossed
with designs on the tablet surface A 40-mesh
granulation ;s used with engraved or em-
bossed tablets, as coarser particles do not fill
as evenly into the engraving on the punch
There is a tendency to compress lettered
tablets harder in order to make the letters
stand out
Adding the Lubneant and (be Disintc-
grant. A lubricant is added to_ensure uni-
form feeding_of the granules, to prev ent
s ticking to th e surface o f the punches and the
_die, to reduce die wall fri ction an d facilitate
ejection, and to re duce punch and die wear
Common lulmcants are calcium stea rate,
ma mesium stea r ate, talc, gbeme, Ster otex
and__$!eanc~acId“TrHese|lm5iDSS~p^sed
throug h a 20o.m c5h sieve t o en sure small
particle size so that theTu brlca nl will have
Its pro p^coa ung^ect. For purely lubn-
catmg purposes., more than 1 per cent of a
lubri cant IS not nec essary
Liquid petrolatum has been added or an
ethereal solution spra)cd on the granulation
This is not a satj^actojy procedusc because
the hjdrophobic coatmg tends to render the
tablet impervious to water and retards dis-
integration
A dismlegrant is a substance which will
rupture the tablet into many small particles
soon after admmistration The large number
of small particles present a greater surface
than docs an mtact tablet and speed solu
tion of the drug A disintegration time of 15
minutes IS satisfactory for most medication
The most common dismtcgrant is potato
starch Starch should be dned at 100®C
(see Fig 42) if It IS to be used as a disin-
tegrating agent The high water content of
commercial starches may be reduced tenfold
by drying, this enhances its dismtcgrating
Compressed Tablets 12Y
Fio 46 A sUsaless steel nbboa blender is being leaded for mixing At the right is an
oscillating granulator used for reducing dried granulations to a desu-ed size for compress on
(F J Stokes)
ability and lessens deterioration of moisture Incorporation of an acid and a bicarbonate
sensitive drugs In the Her gmnidauoa in a tablet wiU produce eServesceace and dis
method some starch is often mixed with the mtegrate the tablet This technic has been
granulation with the hope that it wiU break used in some saccharin tablets however its
apart the individual granules This seems of success has been limited
doubtful value as starch imbibes water freely Flavor may be added by spraying an
and retains little capacity to act as a disuile alcoholic solution of the flavor onto the dry
grant Other disintegrants are gelatin and granules before compression A more recent
numerous algm derivatives tcchnic is to use dry flasors which may be
Compressed tablets of medicaments that blended at the mitial mixmg of the mgre
dissolve slowly should be designed to dismte dients
grate withm a few mmutes m water or m the Compressing Basically a sin^e punch
stomach A tablet must dismtegrate withm tablet machine consists of a die fitted with
a few hours if it is to have any medicinal an upper and a lower punch With the upper
effect A tablet that passes through the punt^ out of and above the die and the lower
gastromtestinal tract is not only useless but punch at the lowest point of descent withm
It gives a false clmical picture and may stand the die a charge of granulation flows mto and
m the way of other beneficial treatment fills the die cavity The upper punch de
Tablets composed mostly of soluble ma scends compressmg the material as the
tenols present no difficulty and generally do lower punch remains stationary The upper
not require a dismtegraung agent punch ascends, followed after a short tune
122 Sol d Dosage Forms
by the lower punch which rises until it is The upper punch is adjusted to control
flush with the upper surface of the die A feed the thickness and the hardness of a tablet
shoe ejects the tablet and Alls the die caviQr Lowering the upper punch produces a hardei
to begin another cycle aiul a thinner tablet
The lower punch is adjusted so that, at The complexity of the machine its opera
Its lowest pomt, the cavity it makes will bold tion and mamtenance arc engmeenng prob*
the quantity of granulation necessary to make lems The proper formulauon of a stable
a complete tablet At its highest pomt the tablet and the adjustments of the punches
lower punch is adjusted flush with the upper are pharmaceutical problems
surface of the die so that the tablet will be '^e finished tablets are passed along a
ejected without chipping vibrating wire tray or under an exhaust sys
Fio 47 Twenty two sUtioa rotary l^let machines capable of producing from
480 to 900 tablets per minute (F J Stokes)
Compressed Tablets 123
Table 16 Difficulties Encountered Durino Tablet Compression
Cause
Cappmg (splitting oS of top after compression)
Excessive pressure
Excessive fine powder
Insufficient binder
Too dry a granulaUon
Worn die or damaged punch face
Improper fill
Damp granulation
Machine runnmg too fast
Granulation too fine or too coarse
Picking (matenal sticking to punch face leaving holes
in tablet surface)
Unsatisfactoty lubricant
Damp granulation
Static charge
Scratched punch face
Mottled tablet
Incomplete mixing
Noodismtegrating tablet
Excessive pressure
Excessive binder
Excessive lubncant
tern to remove any powder The tablets are
then held in quarantme until they have been
analyzed and released for bottling by the
control department
For the novice developing a tablet to con-
tain a drug with a small dose, a simple lactose
granulation may be used as a basic formula-
tion
Basic Lactose Granulation
Lactose 350 Gm
Starch 26
Color 0 25
Magnesium stearate 5
Starch ^aste, 10% I40ml
By geometric dilution, the color is blended
with the lactose and the starch The mixture
IS moistened with starch paste and the wet
mass IS passed through a 6-mesh screen The
wet granulation is dried in an oven at dO^C
The dned granulation is passed through a
40-mesh screen The magnesium stearate is
added and the granulation is tumbled for
several minutes The granulation is com-
pressed mto tablets with a hardness of 6 kgm
Neomycin Sulfate Tablet
Mg. per Tablet
Neoenyem sulfate 250
Lactose 100
Starch 100
Acacia 5
Magnesium stearate 5
The neomycin sulfate, the lactose, the
starch and the acacia are thoroughly blended
The mixed powders are granulated with
methanol cootaming 10 per cent of water
and passed through 6-mesb screen The wet
granulation is placed on paper m trays and
dried m an oven The dried granulation is
passed through a 20 mesh screen Magne-
sium stearate is blended mto the granulation
The granulation is compressed into tablets
Pediatric Chewable Aspirin Tablet
per Tablet
Acelylsalicyltc acid (20-mesh) 81
Afonnitol 97
Sacebann sodium 1
Acacia 4.5
Starch 11
Talc 8
Magnesium stearate 0 4
Dry flavor 0 6
A mannitol granulation is prepared first
The saccharin sodium and the mannitol are
blended The blend is granulated with 20 per
cent acacia mucilage and passed through
8-mesh screen The mannitol granulation is
dried at 45“C and passed through a 20-
mesh screen
The 20-mesh aspinn is mixed with the
dried manmtol gr^ulation The flavor is
added to the stardi and mixed thoroughly.
The talc and the magnesium stearate are
124 Solid Dosage Forms
passed through 100 mesh screen and blended
with the fla\or starch mixture This blend i$
mixed with the mannitol aspirin mixture
Tablets arc compressed to a hardness of 5
kgm using a 11/32 inch standard concave
punch and die set
PRECOMPRESSION
Wet granulation method is unsuitable for
substances mjured by heat or for substances
that arc mcompatiblc with liquid binders
Here the precompression or slugging method
IS used
In the slugging process the entire formula
IS blended and compressed mto Oat tablets
called slugs Precompression requires a heavy
duty rotary tablet machine The punches and
the dies arc as much as 14’d inch in diameter
Considerable dust results and the working
parts of the machine should be housed and
a dust collector attached at the point of com
prcssion These prccauuons are advisable
with all machines
It IS not essential that the slugs be per
fccUv shaped as they are ground to the de
sired granulation size and then compressed
mto the finished tablet
Aspirin Tablet 300 mg
Mg per Tablet
Aspirin granulation contain
mg lO^c starch 333 3
The aspirm granulation is compressed into
tablets using a 13/32 inch standard concave
punch and die set
Phenabarbital Tablet 30 mg
Mg per Tablet
Phcnobarbital 30
Lactose spray dried 168
Magnesium stearate 2
The spray dned lactose and the pheno>
barbital are blended until homogeneous The
magnesium stearate is added to the blend
The blend is compressed into a tablet usmg a
11/32 inch standard concave punch and die
SCL
The use of the chilsonator has been sug-
gested to cbmmate wet granulation and to
speed up and simplify the slugging process
A chilsonator consists of a pair of corded
steel rollers scored m a grooving style The
rollers revolve toward each other at a con-
trolled speed The material to be granulated
is fed to these rollers at a controlled rate The
blend is squeezed at a constant pressure
vaiymg from one to fifty tons per square
mch The rollers may be heated or chilled
os necessary Any moisture present in the
formula is removed by the heat of compres
ston The compressed granules are discharged
in irregular stnps of corrugated plaques
These strips are passed through a conven
tional granulator to secure the proper size
granulation from which the finished tablet is
compressed
Other methods have been suggested for
prepanng granulations In the pan granu
laiing technic» the blended mgredicnts are
placed in a ballled coating pan and moistened
by a spray ^Vhcn the blend has been ade-
quately moistened, hot air is blown into the
pan to dry the granules The resulting
granules approach a spherical shape
Granulations have been made in V-
btenders fitted with spray beads through
which the granulaung solutions arc admitted
by tninmoQ mouotmgs
Either modification may be connected in
such a way that it can be evacuated and
dned under a vacuum without transfer of
the granulation
Tvpes OF Tablets
Although all compressed tablets are pre
pored by the same general procedure, com-
pressed tablets have a wide variety of use
Some common abbrcviauons for types of
tablets are given m Table 17
Tablets Used in the Gastrointestinal Tract.
Mo st co mpressed tablets are swallowed wh_ole
with a dnnk of water They disintcgrate_or
dissolve m the gastrointestinal tract from
which the drug is ^sorbed m order to exert
its iherapcuuc effect Some oral tablcts'^arc
admmistcrcd by placing the tablet in half a
glass of water, stimng and dnnking the sus-
pended mixture These bulk tablets are more
or less restricted to antacid products
82 . n
Magnesium and Soda Tablets 100
Sig Two in water with meals
Some pharmaceutical firms have given
specialty or trade names to their tablets
which are prepared in a distmcUvc form or
shape
Compressed Toblets 12i
83 n
Digitabs ‘Tabloid ' (Burroughs
Wellcome) 60
Sig. Oae daily
84 I)
BetalmSDiskets (Lilly) 10 mg, No 100
Sig Two daily
85 n
Concidin Medilets (Schenng) IS
Sig One t 1 d
86 1 >
DUantm Infatabs (Parke, Davis) 100
Sig One morning and evening
87 n
Dechotyl Tablets (Ames) 10
Sig Two h 8
89 B
Aspirin Dulcets (Abbott) 18
5ig Oneq 4 his
Chewing tablets or wafers have^en avail
able formany years They are intended to be
chewed-before swallowing aBd have been
usedwhcnjhe therapeutic dose w ould make
t he dosage form too large to'swallo w
90 n
Arobon Wafers (Pitman Moore) 12
Sig Chew two then one q 3 brs
91 B
Dical D Wafers (Abbott) 50
Sig Two wafers with each meal
92 B
Kolantyl Wafers (Mcrrell) 32
Sig Three q 3 hrs
The^more recent chewing tablet, some-
times called a soluble table t, bBs a base of
mannitol or glycine and is pleasantly
flavored The soluble chewing tablet will
dissolve in the mouth m approumalely 1
minute They may be chewed, sucked or
swallowed whole Chewmg tablets arc espe-
cially adapted for children
93 B
Deca Vi-Sol Chcwable (Mead John-
son) 100
Sig One tablet daily.
Table 17 Abbreviations for Tablets
C T
compressed tablet
C C T
chocolate colored tablet
C T T
compressed tablet triturate
D A.T
delayed action tablet
D T
dispensing tablet
E C T
entenc-coated tablet
H T
hypodermic tablet
M C T
multiple compressed tablet
R. A.T
repeat action tablet
S C T
sugar-coated tablet
T T
tablet inturate
94 B
Viterta Tastitabs (Roerig) 100
Sig One daily
95 B
Tnsulfazine Palatab (Central
Pharmacal) 30
Stg As directed
96 B
Umeaps Chewable (Upjohn) 30
Sig 1 2 daily
Tablets Used m the Oral Cavity, ^uccal
Jableis are small, flat Uibkls which areplacetf
firtfld'buccarpouch' between tffe cheek and
the gu^ As th^drirg~is reieasecTfrom Ihe
dissolvii^ t ablet. tH e~active ingredient is ab
s o^rbed wi thout passlng^nto the gastrom-
testiaal ' tr ac t~This 'is an adwntageous route
for drugs that would be destroyed by enzy-
m auc action'’ in the gastrointestin al tract Un-
fortunately, few drop are readily absorbed
from the oral sulci Buccal and sublingual
adm mistra tion is limited to glyceryl trmitrate
anifsteroidal hormones
’Anarch and lactose base compressed at
high forces is used with buccal tablets, as it
dismtegrates easily m the saliva No flavor
or sweetening agent is added as they would
stimulate salivation resulting m undue
swallowing and loss of the A_ well-.
Sublmgual tablets are similar to buccal
table ts, but the sublinguaT tab lets arc placed
und er the ton g ue
97 B
Metandren Linguets (Ciba),
5 mg No 25
Sig. Place beneath longue twice daily
126
Solid Dosage Forms
98 n
PeraodrcQ Buccalets (Ciba),
S mg Ko 30
Sig Two daily for 3 days pnor to men
struatiOQ
99 l>
huprel GIosscls (Winthrop),
10 mg SO
Sig One following attack.
100 »
Nilro^ycerin H T 03 mg.
Dispense tube of 20
Sig 1 2 tablets sublingually as neces
saty
101 n
Isordil Subloral (I\cs
Cameron) 90
Sig Oneq 4hn
lo7fnF|p* tablets-iotcoded
to be bold ui the mouth while Uicy^dss^olve
gradually and maintai n the m edication m
contact with the mouth and^tfic throat for a
long penod Troches are u^d for the local
effect of
and local ancstbeiics
Troches arc manufactured by compression
or molding Since troches are intended to dis
sohe slowly and not to disintegrate, they are
formulated somewhat differently from
tablets Troches contam more bmde r, arc
compressed harder andiiavc nodisinte^atmg
agent added Granulation and compression
ar^the same as for tablets
102 It
A-C Troches (AbboU) I bo*
Sig Dissolve in mouth as needed
103 It
Hjbitan Lozenges (Ayerst) 1^
Sig. Dissolve in mouth q i d
Tablets Used for Subcutaneous Admlnls*
irailoa. Pellets or implantation tablets have
been developed for subcutaneous implanta*
Uon of hormones by use of a Kcamc im-
planter or by incision Generally, the 3 2 x
8 pellets are implanted m the thigh
These stcnlc pellets serve as a depot which
slowly releases the hormone over a pro*
longed penod Effects arc observed for sev
cral months after implantation
Normally no excipients arc used m formu*
hung the pellet. The sterile cr)staHme drug
IS compressed mto the finished pellet under
aseptic conditions Oreton, Percorten acetate
and Progynon pellets arc available for hos-
pital and clmicai use
Hypodermic tablets are small tablets with
opposing flat surfaces which arc intended to
be dissolved under aseptic conditions just
pnor to injection Hypodermic tablets are
small so that they readily can be dropped
mto the barrel of the synngc They must be
capable of dissolving rapidly and completely
in water
Hypodermic tablets may be lightly com-
pressed or molded. Beta lactose, dextrose
and sodium sulfate arc used as diluents be-
cause of their solubility Although special
precautions are observed m manufactunng
the hypodermic tablet, it is doubtful that the
solutions prepared from hypodermic tablets
are sterile It probably would be advanta-
geous for the physician to use parenteral solu
tions sterilized m ampuls
Atropine sulfate, codeme sulfate, morphme
sulfate Ditroglycerm and scopolamine hydro-
bromide are customarily marketed as hypo-
dermic tablets
Tablets for Vaginal Use. Tablets com
pressed mto a pear shape for mscruon mto
the vagina arc I^own as inserts Inserts have
a lac tose or a sod iu m bicarbonate base which
r apidly releases tbTBp ig
'atoms taWets arc used to make solutions
mlendcd to be used as douches A jablet
dts solip j in a.spgctfi c»J vo lcnncLaf. water will
make a solution of prop er stre ngth of medi-
c abon foriTvagiDal o ouche
104 n
Viofonu Inserts (Ciba) 12
Sig Insert b s after douche
105 U
Nco-Vagisol (Dorsey) 24
Sig Insert two high in vagina.
Tablets for Miscellaneous Uses. A few
specialized items such as dental cooes arc
used in the mouth llotycm Dcmal Cones
are composed of a sodium bicarbonate and a
sodium chlondc base This base will dis
Evaluation of Solid Dosage Forms 127
integrate and dissolve in the small amount
of serum present m approximately V4 hour.
The dent^ cone is loosely packed in the
socket after tooth extraction and contains an
antibiotic to prevent local multiplication of
bacteria.
Tablets are at times used for convenience
in extemporaneous preparations for local
use. Tablets such as potassium permanganate
tablets and Mercurochrome tablets are used
to prepare cleansmg and disinfecting solu-
tions. Tablets are available for preparing
solutions to be used for chemical stenhxa-
tion of instruments One Mercury Bichloride
Large Poison Tablet dissolved m a pint of
water yields a 1:1,0QQ solution for disin-
fectantpuiposes
Reagent tablets for diagnosUc tests are
used by clinics and the patient for self-diag-
nosis. Acetest reagent tablets are used to
test for ketonuna; Hematest reagent tablets
are used to detect occult blood; and Ictotest
reagent tablets are used to test for urinaiy
bill^bin.
The DisPENstNG of Tablets
Ta blets should be dispensed in gla ss or
plas tig^K nr glass^ nftles. Tablm ^ould
not be touc hed bv the han ds during packag-
ing procedures. Professional appearance is
enhanced bj' using an Abbott samtaiy count-
ing tray which elunmates the fingers touching
the tablets or other prefabricated dosages.
Not only is handling unsanitary, but moisture
from t he hands may cause coat ed mblets to
dull and to stic k. Colton should'be 'placed
in the vial on top of thejablets.
WEenTa'pTcscriptionris written for only a
few tablets, they may be placed in a cello-
phane envelope and dispensed in a card-
board box.
Tablets should b e sto red in ri^ con-
tainers.TTth'e'ta blels ' coniam ^ drug^that is
photosCDsluve, th e tablets mu st be dis pensed
m a5~5tfiberbottle or vi ai. Exposure to ex-
cesslve h eat, strong light a nd moisture is to
be avoide d.
EVALUATION OF SOLID
DOSAGE FORhfS
Chemical Identity and purity of prefabri-
cated solids ore implied warranties. Self-
Fio. 48. Sanitary capsule, pill and tablet
counting tray. (Abbott)
analysis and control are left largely to phar-
maceutical industry. The pharmaceutical
company develops its own assays and speci-
fications for new drugs and dosage forms
with the approval of the F.D A. As chemical
analysis by the practiemg phannacUt is not
feasible, he must rely on the reputation of
the manufacturer. TTiere are certain tests
which may be carried out in the pharmacy
without any elaborate equipment or great
expenditure of time. These will help to evalu-
ate some of the desirable characteristics of
solid dosage fonns.
Accurate Weight. The U.S P. weight varia-
tion tests provide limits for the variation
from the observed average in capsules and
from the average gross weight for tablets.
To determine the wei^t variations for
hard capsules, 20 mtact capsules are weighed
and the average gross weight is calculated.
The weight of each individual capsule must
weigh between 90 and 110 per cent of the
average gross weight.
If all capsules do not meet this require-
ment, the test may be expanded. Then 20
capsules are weighed individually. The con-
tents of the 20 capsules are removed and
combined. The weight of the total contents
and the average weight are found. Each cap-
sule shell is weighed individually. The net
128 Solid Dosage Forms
^velght of each capsule content is calculated
by subtracting the \seight of the shell from
the respective gross eight The difference
between the net weight and the average
weight should not exceed 10 per cent for
more than 2 capsules, and m no case should
the difference be greater than 25 per cent
If more than 2 but less than 7 capsules
deviate from the average between 10 and
25 per cent, the net wci^ls of an additional
40 capsules are determined and the average
content of the entire 60 capsules is found
To meet specifications not more than 6 of
the 60 capsules may exceed 10 per cent of
the ascrage, and in no case may the dtiTer-
cncc exceed 25 per cent
The weight vanation tolerances for un-
coated tablets arc given in Table 18 Twenty
tablets arc weighed individually The aver-
age weight IS calculated For the tablets to be
acceptable, the weights of not more than 2
of the tablets may differ from the average
weight by no more than the percentage tabu-
lated and no tablet may diifer by more than
double the per cent
Organoleptic Evaluation. The homogeneity
of capsule contents and tablets may be judged
by visual cxammation Speckled powders or
tablets indicate improper and mcomplctc
blending of ingredients and heterogeneous
listnbution of the active mcdiciasls la
Table 18. Weight Variation Tolerances
FOR Uncoated Tablets
Average Weight op
Percentage
Tablet in Mo
Difference
13 or less
15
From 13 through 130
10
From 130 through 324
75
More than 324
5
scored tablets the drug must be uniformly dis-
tributed If the tablet is divided, the patient
will receive that portion of the total active
ingredient m the intact tablet only if the
enure tablet is homogeneously blended
The naked eye readily detects Jack of
uniformity or motilmg m a colored tablet
Multiple layered tablets are often laminated
into several distinct layers to avoid chemical
and physical mcompaubilities Some tablets,
such as NaJdccon or Concidm Mcdilcts, are
color-speckled tablets Although these tablets
as a whole are not uniform, each layer or
granule is homogeneous
Detenoraiion of solids may be detected
visually or by odor Aspino tablets which are
improperly formulated, improperly stored or
exposed to moisture undergo hydrolysis On
opening a contamer of such tablets, the odor
of acetic acid formed during bydrolysts ts
quickly discernible Tablets may fade or
darken in color mdicaung that an unwanted
acUon has occurred.
Hardness. Capsules may be examined for
cracks or dents and for brittleness Tablets
that are chipped or cracked are not suitable
for dispensing
The resistance of tablets to mechanical
wear is shown in breakage and abrasion, and
It IS governed by the tensile strength of the
compressed tablet The hardness of a tablet
1 $ expressed as that force required to break
the tablet. Hardness is used to characterize
tablets because it is simple and convenient
to measure Hardness is measured by the
Strong Cobb, the Pdzer and the Stokes Hard-
ness Testers Hardness is expressed in kilo-
grams of force applied Although the instru-
ments give different hardness v^ucs for a set
of tablets, it has been found that a constant
ratio of hardness results with the Strong Cobb
Tester giving results 1 6 times those of the
Stokes Tester.
Evaluahon of Solid Dosage Forms 129
FORCE IN FOUNDS
Fio 50 Linear rtlationship of loga-
rithm of compressiooal force and hard
ocss of a tablet (Higuchi, T Rao, A N ,
Busse, L.W,andSwintosky, J V } Am
Pharm Ass 42 194, 1953)
Tlie practicing pharmacist may test tablets
by snapping them between bis thumb and
forefinger U the (ablets do not snap readily,
they are too hard and may disintegrate with
difficulty Oral tablets normally have a hard-
ness from 4 to 6, however, sustained release
tablets and troches are compressed to at
least 10
As shown m Figures 50 and 51, hardness
IS proportional to the loganthm of the force
of compression and inversely proportional
to the porosity of a tablet The greater the
force of compression used m. manufactunng
a tablet, the less porous and the harder the
tablet wiU be Although increasing the hard-
ness makes a more elegant and a less friable
tablet, the high force of compression reduces
the void space or porosity With a reduction
m porosity, penetration of dissolving or dis-
mtegratmg Quids mto the tablet is diminished,
consequently slowing or preventing dism-
tegrationof the tablet.
Disintegration. Dismtegration tunc limits
are not specified for capsules, since the
gelatin shell dissolves rapidly m the gastro-
intestinal tract A hard gdaun capsule placed
POROSITY m PER CENT
Fig si Linear relaUonship of the hard-
ness and the porosity of a tablet (Higuchi,
T , Rao, A N , Busse, L W , and Swin-
tosky, J V J Am Pharm Ass 42 194,
1953)
m water at 37^C should release its contents
within 10 minutes
Factors determining the disintegration of
tablets are the physical and the chemical
properties of the granulation, the hardness
and the porosity A tablet is generally formu-
lated with a disintegrating agent, which will
cause the tablet to rupture and fall apart in
water or gastric fluid
Dismtegration does not imply complete
solution of the tablet or the drug Complete
disintegration is that condition m which any
tablet residue remainmg on the screen of a
disintegration apparatus is a soft mass having
no palpably firm core Normally, the dism-
tegration tune of a tablet is tested, but the
tune required for solution of the drug is not
expressed
Most lubricants utilized m tablet produc-
tion are hydrophobic substances Excessive
lubncani will retard disintegration by pre-
ventmg the penetration of water mto the
tablet. A tablet with a great void space will
130 Solid Doioge Forms
Pic 52 Expoaeniial rebttoosbip be
tween disinte^tioQ lime and the com
pre&sional force (Higuchi, T , Rao, A. N ,
Bime. L W and Swiotosky J V J Am
Pharm. Ass 42 194. 1953)
be peaetrated by fluid and dissolve or di$>
utegrate more rapidly than a bard, com
pressed tablet with >e^ low porosity
As shown m Figure 52, it nos been deter*
mined that the logarithm of disintegration
time is proportional to the force of com
pression
The simplest means of testing the dism-
tegration of a tablet is to drop it m a ^ass
of water With occasional, gentle agitation
the tablet should disintegrate in 15 to 50
mmutes
The USP disintegration apparatus con*
sists of a basket rack holdmg 6 opcu'cnd
glass tubes with a 10 mesh screen on the
undersurface The basket-rack is immersed
in a 1 liter beaker contaimng an appropriate
fluid at 37°C The basket rack is raised and
lowered through a distance of 5 to 6 cm, at
the rate of 30 cycles per minute The volume
of fluid used is such that, during the opera*
uon, the basket rack is never less than 2 S
cm below the surface of the fluid or abose
the bottom of the beaker
Each glass tube is supplied with a per-
forated, grooved disk which u placed on
top of the tablet to simulate movement of the
gastromlestioal tract
A tablet IS placed m each glass tube and
a disk IS added The basket rack, is immersed
and moved through the fluid for the time
specified m the monograph At the end of
this time, when the basket rack is lifted, all
tablets should ba\e dismtcgrated completely
If 1 or 2 tablets did not disintegrate com-
pletely, the test IS repeated with 12 additional
tablets Not less than 16 of the 18 tablets
must dismtegrate completely to meet speci-
fications
Plain coated tablets are tested by first plac-
a tablet m each glass tube and imroeisu^
m water at room temperature for 5 minutes
to wash oS any soluble external coatmg A
disk IS added to each glass tube, and the
apparatus is operated for 30 mmutes usmg
artificial gastric fluid at 37"C After 30
minutes the basket rack is lifted and the
tablets are observed. If the tablets have not
completely dismtcgrated, they are immersed
at simulated mtestmal fluid and observed
The tablets should disintegrate m the tune
specified m the monograph If 1 or 2 tablets
fail to disintegrate completely, the procedure
is repeated with 12 additional tablets To
meet specificatioos, not less than 16 of the
18 tablets must disintegrate completely
Entenc-coated tablets arc tested by plac-
ing a tablet m each glass tube and immersing
m water at room temperature for 5 mmutes
to wash off any soluble external coatmg The
apparatus is operated for an hour usmg simu-
lated gastnc fluid After an hour the basket-
rack IS lifted and the tablets arc observed
No distmcave dissolution or dismtcgration
should be seen A disk is added to each glass
tube The apparatus is operated m simulated
mtestmal fluid for a period of time equal to
2 hours plus the time limit specified m the
individual monograph Then the basket rack
IS lifted and observed All of the tablets
should have dismtcgrated completely If 1
or 2 tablets fail to dismtegrate completely,
the test IS repeated with 12 additional tablets
To meet specifications, not less than 16 of
the 18 tablets must dismtegrate completely
Buccal tablets are tested m the same way
as uncoated tablets but without disks The
basket rack is immersed m water for 4 hours
After 4 hours the basket rack is lifted and
Coafing of Solids 131
the tablets are observed All tablets should
have disintegrated
The U S P tablet disintegration test does
not apply to tablets exceeding 15 mm m
diameter, troches, tablets for hypodermic
solution, chewable tablets, repeat action and
sustamed release tablets
Hypodermic tablets are tested for solubil
ity A hypodermic tablet should dissolve com-
pletely, producing a clear solution, wthin 2
mmutes when shaken gently m a test tube
containing 2 5 ml of water
Chapter 2 should be consulted for a dis
cussion of the limitations of such tests in
evaluating therapeutic efficacy
COATING OF SOLIDS
A coatmg can be appbed to a tablet, a piU,
a granule or a capsule A coatmg may be
appbed to a solid dosage form to mcrease the
stabili^ if the drug is ^ected by atmospheric
moisture or oxygen, to mask an tmpleasant
taste, to retard loss of volatile mgredients,
to improve the appearance of the solid form
or to identify the finished product as being
manufactured by a particular pharmaceutical
firm A coating may control the site of action,
as with enteric coatmg, or it may regulate the
release of the drug, as with repeat action
products
Fio 53 An mdustnal apparatus for tesUo^ tablet dismtegrauon tune. (Dorsey
Laboraionn)
132
Solid Dosage Forms
106 n
Anunoiuum chloride Enseals 05
Dispense SO
Sig Tw o tablets every 4 hours.
107 n
Ferrous sulfate C C., 0 2 No 36
Sig One tablet ti d p c
103 I)
Coryia H “A” (Richards) 30
Sig One q 3 hrs for cold
109 I)
Pagitan S C Orange No SO
Sig One three tunes a day
Sugar Coatikg
Commercially, the majonty of the coaled
dosage forms are covered by a sugar coal-
ing The coat is approximately 0 4 to 0 S mm
m thickness The maximum weight applied to
a tablet by coating is approximately equal to
the weight of the uncoated tablet The
amount of matenal depends on the number
of coats requued to smooth and color the
tablet
Tablets that arc to be coated arc com-
pressed with a deep concave punch and die
set, producing a tablet approaching a spher-
ical shape This allows the tablet (o be cov-
ered more uniformly in the shortest time
Tablets to be coated may be compressed
harder than uncoated tablets because they
must withstand the additional processing
All dust must be removed from the tablets
prior to coating or the tablets will not be uni-
formly smooth
Sugar coating requires expcncncc and
elaborate equipment which die community
pharmacist docs not have at his disposal The
industrial equipment consists of motor-dnven
coating and polishing pans to which on ex-
haust and a hot air system with a blower is
connected The coating pans are made of
stainless steel or copper Polishing pans arc
lined with canvas This Immg polishes the
tablets as they slide against the fabnc Steam
kcldcs are required to mamtam the coaling
solutions m a pourable state
Subcoatiog IS effected by the alicmale
wetting of the tablet with subcoaung solution
and application of a coating powder when the
tablets are partially dry This procedure
rounds oil the sharp edges and builds the
tablet to the desired shape Modified solu-
tions of syrup and gelatin arc used os a sub-
coating solution Calcium carbonate, starch,
sugar and kaolin may be used m the coating
powder
^fedlum Subcoating Syrup
Acacia
Z25%
Gelatin
225
Sucrose
57 25
Distilled water
38 25
Subcoaung Ponder
Cidcium carbonate
35%
Kaolin
16
Talc
25
Sucrose
20
Acacia
4
If a tablet contains a hygroscopic in-
gredient, a scaling coat is applied so ^at the
water from the solutions applied will not be
absorbed by the tablet Such moisture would
eventually penetrate the coating, resulting m
discoloration and deterioration of the tablet
Pharmaceutical glaze or shellac is dis-
solved m warm alcohol and allowed to stand
until soluuon is complete
Sealing Coat
Shellac 40%
Alcohol 60
The dust free tablets are placed m a coat-
ing pan A small amount of shellac solution
IS applied to the rolling tablets The opera-
tor usually ensures even distnbulion of the
shellac by mixing the rolling tablets with his
hand After S minutes of roUmg, the cold air
IS turned on to dry the shellac After 10
minutes the tablets arc diy A second addi-
tion. one half the volume of the first coat, is
applied and dried Two coats tisually are
adequate for scaling purposes Excessive
coating with shellac will mterfere with the
disintegration of the tablet
After the tablet has been sealed, the
gelatin syrup at 60®C is added to the pre-
heated tablets m a rotating coating pan The
tablets arc immediately stirred with the hand
to distribute the solution When the gelatin
syrup IS partially dry (as mdicatcd by the
t^lcts bcginnmg to form a ball), the sub-
coating powder is immediately sprmkicd into
the coating pan until no w ct tablets show and
the tablets roll freely An excessive amount
of subcoaUng powder should be avoided
Coafing of Solids 133
When the subcoating powder has been
taken up by the tablets, the wann air is
turned on until the tablets are dry This re-
quires approximately 15 minutes for small
batches
When the tablets are dry, the warm air is
shut off and the coating procedure is re-
peated until the tablets are nicely shaped and
coated This may require from 5 to 30 coats
Smoothing is the alternate wetting with a
smoothmg syrup and drying of the subcoated
tablets until they are properly rounded and
smooth Syrups are used as the smoothing
solutions
Smoothing Syrup
Sugar 60%
Distilled water 40
With the tablets rotating m a clean and
dust free pan, the syrup solution at bC’C
IS added After 5 to 10 minutes, when the
rotating tablets appear dull and toll freely,
warm air is turned on When the tablets are
dry, the process is repeated until the coating
IS smooth Drying requires approximately
20 minutes Five to 25 coats may be neces-
sary to smooth the tablets
Colormg. With colored tablets, a certified
dye IS added to the smoothmg coat and the
depth of color is gradually built up by suc-
cessive coats In the initial application, the
syrup IS colored lightly After several coats
have been applied, several more coats of a
more highly colored syrup are applied Sue
ceedmg coats are made darker m color until
the last coat has the desired shade This slow
development of color prevents moiUmg of
the coat
A stock coloring syrup may contain from
0 1 to 0 6 per cent of a certified dye The first
colored syrup may be a 1 15 dilution of the
slock colonng syrup, thus, the first colored
syrup may have the dye present m 0 005 to
0 04 per cent concentration
Fimshing is the slow, controlled drymg of
the last sjrup coat applied to the tablet The
coaung pan is rotated manually with slow
drymg so that a very smooth finish is formed
When the last syrup is applied, the opening
to the coating pan is covered with a cloth
The pan is rotated by hand through one half
a revolution cveiy 10 to IS nunutes during
a 2 hour period
I Qtt
Fio 54 (Above) Sugar-coated tablets
showing the subcoating, the smoothing
and the coloring coats (Below) Enteric
coated tablets
Polishmg, the final step, is the application
of a thin layer of a glossy wax The wax may
be dissolved m warm naphtha or petroleum
benzine, and the solution is added to the
tablets which are allowed to rotate until the
solvent has evaporated The polishing mix-
ture may be dusted on as a solid which is
picked up by the rotaung tablets
Polishing Mixture
Beeswax 90%
Camauba wax 10
In the sugar coaung process considerable
time IS spent m sealing, rounding and smooth
ing the tablet and m overcommg the white
background during the colonng phase A
suggested modification of this process pro-
duces a coating about half as thick and re-
quires half as much Ume
The tablets are given 2 coats of acacia,
using a gclatm soluuon as the adhesive A
colorant is added to the gelatin solution so
that colormg begins immediately The tablets
are scaled with one coat of a gum or a resin
m a suitable solvent Shellac m alcohol may
be used A pigmented coating suspension is
now applied Generally, 25 coats are ade-
quate to develop the desued color The
tablet IS then polished m the convcnuonal
way
Film Coating
Film coatmg is the rapid process by which
a thm film of coaling matcnal is applied or
Fio 55 A technician operating a batlciy of coating pans (each with the capacity of from
75 000 to 250 000 tablets) and one polishing drum (F J Stokes)
spcay'ed onto tablets The process of sugar
coating has the disadvantage of being slow
and involving much labor and it greatly in
creases the weight of the dosage form Film
coating has none of these disadvantages
Film-coatcd tablets retain their original shape
and the thin film permits designs unpnnted
on the tablet to be seen The film coat will
masL. unpleasant taste and protect the tablet
from the atmosphere
There IS no significant change in disintc
gration of a film<oa(cd tablet oompanrd with
that of the uncoated tablet. Most film coats
will add a luster to a dull imcoated tablet, if
required a film-coatcd tablet may be polished
m the same maoner as a sugar coated tablet.
In general the tablets arc given a sealing
coat after which a solution of ccllulosic
polymers is applied or sprayed on the tablets
HydroxycthyIccUulosc sodium caiboxy
mcthylccUuIosc and cellulose acetate phth^
ate have been used m various combinations
with pol) ethylene glycol and polyvmylpyr
rolidonc m alcoholic solvents Zem dispersed
m isopropanol by means of the Spans and
Tweens has also t^cn used
110 It
Erythromid Filmtabs 50
Sig Three Q J D
Coating of Solids 135
Air Suspension Coating
The Wurster process is an air suspension
method for the rapid coatmg of granules,
ponders and tablets The sohds to be coated
are fed mto a vertical cylinder and supported
on a column of air which is being adimtted
conUnuousIy from the bottom of the cylinder
m such a volume and at such a pressure that
the solids remam suspended Because of the
action of the an stream and the pressure drop
at the top of the cylmder, the sohds rotate
m both horizontal and vertical planes The
coatmg solution is adimtted at a controlled
rate The air coming mto the cylinder is
heated to provide rapid drying of the coat-
mg syrup Roimdmg coats on tablets are
applied in less than an hour
The Wurster process may be used to pro-
duce granulations It will granulate rapidly
and It needs no separate drymg blending or
gnndmg procedures
Press Coating
Press coatmg is the process by which a
fine, dry granulation is compressed around a
core tablet fonnmg what has been called a
'tablet withm a tablet ’ Press coating is
faster and more economical than the pan
coating process, as no sealmg or pohshmg
IS required Incompatibilities caused by mois
ture are avoided, smce (he press coatmg
rocess is moisture free Press coated tablets
ave less weight variation and may be com-
pressed softer than pan-coated tablets The
compccssioa coolmg process can be used to
coat tablets of any shape and size Press-
coated tablets can be engraved or embossed
more sharply than con film-coated tablets
Press-coating machmes are of two types
In one type the core is compressed on a
standard tablet machme and fed mto the com-
pression coater The second type is basically
two rotary machmes with a smgle drive shaft
and transfer device so that the compression
of the core and the coatmg is a contmuous
c)cle
In addition to being used to coat a tablet,
the process may be used to prevent contact
between mcompatible mgredients of the
tablet One of the incompatible drugs is com-
pressed m the core, and the other drug is
compressed m the coat or the shell separating
Fig s 6 Press-coated tablets and modified
press-coated tablets
the reactmg drugs This technic has also been
used with lammated multiple compressed
tablets Each mcompatible drug is granulated
and compressed separately, fonnmg a
finished tablet with two or more layers, each
containmg one of the mcompatible drugs
Press coatmg has found wide application
m repeat action and controlled release medi-
cation In a repeat action tablet, the core is
treated so that it does not dismtegrate until
4 to 6 hours have elapsed, while the shell
dismtegrates rapidly releasmg its drug for
the initial dose of the medication
111 i>
Pabuin A C Buffered 50
Sig Two Q I D
112. B
BoaadoAin Tablets 30
Sig One b s
113 B
Pynbenzamine Ephednne 24
Sig. Oncq 4hrs
Enteric Coating
A dosage form is cntcnc-coated if the
coatmg prevents the dismtegration of the
tablet m the stomach but permits disintegra-
tion m the mtesUnol tract Such a coatmg is
needed when a drug is decomposed or maett-
vated by the pH or the digestive eD 2 )’mcs of
the stomach, is imtatmg to the stomach or
is to be placed m the specific area of the m-
testme
136 Solid Dosage Forms
114 n
Diasone Sodium 330 mg
Give 60 Enterabs.
Sig Ooe daily
115 Jl
Gentian violet Enseals, V6 gr No 24
Sig Twot 1 d.
116 n
Pituitary Body Anterior Lobe 50
Dispense 2V4 gr EmpIcL
Sig As directed
Biologic variation ailccts the release of
medication from an entcric-coated dosage
form The emptying tune for the stomal
may vary from a few nunutes to as much as
12 hours The research and developmental
pharmacist uses the aserage stomach cmpiy-
mg tunc of 6 hours m formulatmg an eotcnc
coaung Solid dosage forms remain for a
shorter period of time m an empty stomach
than m a full stomach It is generally con
sidcrcd advisable to administer an cotenc*
coated product 2 hours before meals — the
time when the most uniform emptying ts ob>
served
Vonation m pH m the regions of the
gastrointestinal tract make it preferable that
an enteric coat disintegmte mdcpcndcot of
pH More recent cntenc coatings arc based
on the time requued for dismlcgratioo of the
coaung when in contact with moisture One
such entcnc coating is a muture of powdered
waxes such as camauba wax or stcanc acid
and vegetable fibers of agar and elm bark
\Vhen the tablets arc adimmstcrcd, the vege-
table fibers imbibe water, swell and begin Uic
process of dismtcgrauon By varymgibeiauo
of the vegetable fibers to the wax and by vary-
mg the thickness of the coating the tunc
required for dismtegmuon may be controlled.
Gclatm polymerized with formaldehyde,
stearic acid, salol, keraun or resms has ^cn
used as an catena coating substance with
lumted success
The pracucing pharmacist may be called
on to coat a capsule, a tablet or a piU wvib an
cntenc coatmg The traditional salol coat
used for extemporaneous cntenc coating has
been replaced to some extent by one consist-
ing of n butyl stearate, carnauba wax and
stcanc acid All resist the action of the gastnc
fluid, but, with the excepuon of camauba
wax, they are hydrolyzed m the mtesUne
Forty five parts of n butyl slcaraie, 30
parts of carnauba wax and 25 parts of stcanc
acid are fused at 75®C. and are mamtamed
at this temperature dunng the coatmg
process The capsule is held at one end with
mcczcjs and dipped somewhat more than
half its length into the coaung mixture The
capsule IS withdrawn, its free end is touched
to the hp of the dish to remove excess coat-
ing mixture, and it is placed on a Ulc The
operation is repeated until one end of each
of the capsules has been coated Then the
coating IS completed by grasping the capsule
carefully at the coated end and by dipping it
in such a fashion that the coals overlap The
cycle should be repeated once to ensure an
adequate coaung Although it is possible to
coat tablets and pills by this iconic, it is
difficult to obtain pharmaccuucal elegance
A more recent method of coating with
cellulose acetate phihaJate may be used to
produce acceptable eotenc<oated tablets,
capsules or pills Cellulose acetate phtholate
has been widely used commercially The dis-
mtegration or dissolution of cellulose acetate
pbthalatc docs not require fluids with a high
pH but only soluuons vvhicli will contnbutc
ions to the phthabtc carboxyl group and en-
hance the solubility of cellulose acetate
phtholate m aqueous medium. Cellulose ace-
tate phihalatc coaungs also disintegrate due
to the bydroIyUc effects of the esterases of the
intestinal tract
Cellulose acetate phthalate may be used
extemporaneously A 10 per cent solution
of cellulose acetate phtholate m acetone is
placed m a small viaj A capsule is dropped
mto the soluUon and removed with tweezers
The capsule is allowed to touch the lip of
the vial to catch any excess solution The
capsule IS held m the tweezen for a mmute.
after which it is placed on gauze In this
manner oil of the capsules arc coated The
cycle IS repeated until 3 coats have been
applied.
This method has the advantage that no
heat IS used in the coatmg process, there is
little mcrcasc m weight of the dosage form,
and tablets may be coated as well as pills
and capsules
Molded Solid Dosage Forms
137
^*d!afC5»4
CELLULOSE ACETATE
PHTHALATE COATING
f ^
! non
I oon
N-BUTYL STEARATE-
UNCOATED CARNAUBA WAX-
STEARIC ACID COATING
O C ^
o GOO
Fig 57 Capsules and tablets entenc*co3ted with cellulose acetate phtbalate or a mixture
of o butyl stearate-camauba wax steanc ac d (Parrott £.1^1 Pfaaim Ass NSI
158 1961)
MOLDED SOLID DOSAGE FORMS
Tablet fnturates are prepared by forcing
moistened ingredients into a mold under
manual pressure Tablet tnturates are Sat
faced tablets with a diameter of approxi
mately 5 mm The diluent used m tablet
tnturates is lactose or a mixture of lactose
and sucrose
Tablet tnturates are adimmstered by plac
ing on the tongue and swallowing with a
drmk of water The advantage of tablet trilu
rates is their rapid disintegration and solu
tion Tablet tnturates are fragile and their
small size makes them unsuitable for drugs
With large doses
Some tablet tnturates are made by com
pression but many tablet tnturates are still
produced by manual moldmg although the
method is costly The community pharmacist
is rarely required to prepare a tablet tnturate
extemporaneously The procedure for pre-
paring tablet tnturates in the pharmacy will
be found m American Pharmacy *
• Sprowls, J B Amencao Phannacy 3lh cd.
Philadelphia. Lippincotl, I960
Hypodermic tablets are mtended to be dis
solved in water and the solution is to be m
jecied parenterally Hypodermic tablets are
smaller than tablet tnturates m order to
facditate placing the hypodennic tablet in
the barrel of the syringe Solution of hypo
dermic tablets must be rapid and complete
It IS doubtful that solutions prepared m this
manner are sterile
Hypodermic tablets arc packaged m tubes
of 20 tablets It is preferred that they be dis
pensed in the onginal tube m which they arc
packaged to restnet contamination and to
limit the breakage of the fragile tablets
Tablet tnturates are dispensed m a snap-on
or screw-cap vial or glass container usmg
cotton on the bottom and on the top of the
tablets to prevent breakage
117 U
T T Sacchann soluble 1 gr 100
Sig Use as a sugar substitute
118 n
T T Codeine sulfate 1 gr No 12
Sig One for pain p r n.
}3S SoUd Dotage Forms
119 n
H T Scopolamine hjdrobro-
midc <X32 mg
Dispense 1 tube.
Sig Use as directed
Pills arc oval or spherical solid masses
contauiiog drugs to be administered orally
The usual p^l^^clghs from lOQ to 300 tng
Pills have declined m use until it has be*
come a curiosity for a pharmacist to be called
on to compound an extemporaneous pill Al-
though some pills are still produced by phar-
maceutical mdustiy, the tablet and the cap-
sule have largely replaced the pill as a dosage
form Pills have no advantages not found m
tablets or capsules
In prepanng a piU the powdered mgrcdi-
ents arc thoroughly blended The appropnalc
excipient is carefully added and the mass is
formed by applymg considerable pressure
with the pestle When the mass is plastic and
cohesive but not sticky, it is removed from
Uic mortar and kneaded with the bands The
correct consistency is reached when the mass
tends to peel from the sides of the mortar
The mass is kneaded m the hands until no
cracks show The mass is then rolled be-
tween the palms into a ball Thu ball is
placed on a pill tile and rolled into a c>lindcr
The cylinder is cut mto the required number
of segments
The cut segments arc shaped by roUmg
one pill at a tune in the palm of one band
Vritli the hngcr of the other
Since pills arc now so little used, it has not
been deemed necessary to repeal the details
of ihcir production TTicsc may be found m
earlier texts
120 n
Alophen pills IS
Sig 12b.s
121 n
Cathartic Compound, Brown,
O C No 20
Sig Twoptllsasalaxauve
Lozenges dissolve slowly m the saliva,
medicating the throat for a prolonged time
Those sold over the counter, such os Allcn-
bury’s Pastilles and cough drops, are pleas-
antly flavored to appeal to the sense of taste
Various t}-pcs of lozenges, such as troches
and pastilles, arc prepared by molding masses
Some are prepared similarly to pills with a
diilerencc m the final form Others arc manu-
factured by molding a hot mass which solidi-
fies on cooling In general a lozenge consists
of the mcdicmal agent, flavors, sugar and
gelatin or a gum.
One candy base is prepared commercially
by combining 1,200 lbs of sugar, 1,000 lbs
of 43® Baumc com syrup and 560 lbs of
water Warm water is metered into a tank
equipped with an agitator The sugar is added
to the water By means of a steam jacket the
sugar solution is heated (o 40‘’C The com
syrup at the same temperature is metered
mto the tank After thorough mixmg the mass
IS pumped mto the cookers
The mass is heated to I15®C for a short
penod under atmosphenc pressure The syrup
is pumped through a cod, which is surrounded
by high pressure steam, and reaches a tem-
perature of I45®C A vacuum is appLcd for
approxunatcly 10 minutes and water is with-
drawn At this stage, the candy base consists
of approximately two thirds sucrose solids,
one third com syrup solids and less than 1
percent water
Drugs, color and flavors are thoroughly
mued mto the molten mass As the tempera-
ture of the candy will be approximately
90*C, ihcrmolabdc drugs cannot be incor-
porated m a candy base The mixture is
mechanically kneaded and drawn mto a thm
rope on a spinnuig machine The rope is cut
and shaped by a dic-comprcssmg machine
The lozcoges are cooled on moving belts by
jets of cool air
In order to assure stability, troches are
packaged in foil or waxed paper to minimize
moisture absorption from the atmosphere
122. K
Candettn I box
Sig For relief of sore throat
123 n
BaciJIets 20
Sig One troche q 2 hr
124 n
SucrcU 1 box
Sig. Dissolve without swallowing.
Sustained Release Pharmaceuticals 139
125 B
Synkayvite C Lozenges 100
Sig Two troches t i d
SUSTAINED RELEASE
PHARMACEUTICALS
Sustained-release medication was mtro-
duced mto the Umted States about 1952 At
present, sustamed-release medication repre-
sents about 5 per cent of the total phanna-
ceutical market Although 3 major firms pro-
duce 73 4 per cent of the sustained release
medication, there are approximately 50
manufacturers that produce sustained release
products
Long actmg oral products have been de-
scnbed by various ambiguous terras A sus-
tained-release product is one in which a drug
is mitially made available to the body m an
amount sufficient to cause a rapid onset of
the desired therapeutic response, after which
the level of therapeuuc response is main-
tained at the initial level for a desired number
of hours beyond the activity resulting from
a conventional dose A sustamed-release
product must be formulated so that the rate
of release of the drug, after the initial con-
centration, IS equal to the rate at which the
drug IS eliminated or inactivated As such a
release is difficult to produce, most prepara-
tions are prolonged-action products
A prolonged-action product is one m
which a drug is mitially made available to
the body m an amount sufficient to produce
the desired therapeutic response quickly and
which then provides for replacement of the
disappearmg drug at a cate which mneases
the duration of therapeutic activity compared
with that of a single dose
Repeat action dosage forms are not pro-
longed acting products A repeat-action prep-
aration miualiy provides a single dose of a
drug, and, after several hours, when the
therapeutic response of the initial dose has
ceos^, it provides a second smgle dose
By cxpcneocc, medical science has found
that there is a certam amount of a drug which
will be required to produce a desired effect
m the majority of patients This dose or scrum
level IS knoiMi as the mimmum efiecUve dose
HOURS
Fio 58 A massive dose results in
longer duration of activity, but the serum
level rises to a toxic level uutially
(M ED) Any dosage which falls below
the minunum effective dose does not produce
the desired effect
Ideally, a sustained release solid dosage
form given once daily should provide suffi-
cient drug immediately to produce a rapid,
miual therapeutic response and should mam-
tam this level of response for 12 hours on a
smgle administration Prolonged effect may
be achieved by administering massive doses
of a drug This is not an effective method,
because, initially, the concentration of the
drug greatly exceeds the M E. D Any dose
that exceeds the M E D is wasted drug,
smee the desired therapeutic response is ob-
tamed at the M E D hfassive doses produce
a drug concentration that approaches the
toxic dose of the drug and markedly increases
unwanted side effects
140 Solid Oosago Forms
Fio 59 The scrum level obtained by
the admimstratioo of 1 tablet or capsule
3 times a day compared with the scrum
level obtained from an ideal sustained
release tablet or capsule
A soluble drug v>ith a halMife of 2 hours
has a M E D scrum level of 30 y/ml A
250 mg and a 500 mg capsule produce a
maximum scrum level of 100 and 180 y/ml .
respectively Because the capsule dissolves
rapidly and the soluble drug u quickly dis*
solved and absorbed the time required for
release and absorption into the blood stream
IS small and may be ignored Assuming a
first order elimination from the blood, one
can see in Figure 58 that by doubling the
oral dose the scrum level is maintained above
the Af E D for approximately 2 additionaf
hours
A conventional capsule, tablet or pill usu-
ally IS admmistcrcd 3 or 4 times daily to
evoke and maintain the desrreJ therapeutre
response Imtially each dose will produce a
maximum drug concentration far above the
M E. D As the drug is eliminated and in-
activated, the drug conccniration falls below
the M E D Below this level die therapeutic
cflcct IS inadequate until the next dose is ad-
ministered Thus multi-doses arc wasteful
and inadequate
If a 250 mg capsule of the soluble drug
with a half life of 2 hours were presenbed
to be administered 3 times a day, a patient
would probably take a capsule at 8 00 a m ,
2 00 P M and 8 00 p M and no medication
durmg the mght As shown lu Figure 59,
durmg the 12 hours immediately ^tcr the
beginning of administration, the scrum level
would be adequate approximately 60 per cent
of the tune There arc 4 7 hours when the
scrum level falls below the hf E D In a 24-
hour interval there would be II 2 hours of
adequate scrum levels, approxunatcly 50 per
cent of the 24'hour period would have thera-
peutically effective scrum concentration
An ideal sustamed release dosage form
will maintain a constant and uniform drug
release and concentration as shown m Fig-
ure 59 With sustained release, the maxima
in drug concentration shown with multi doses
arc eliminated with a more economical uti-
lization of the drug and fewer side clTccts
Sustained release eliminates the fall of drug
concentration below the M E D so that the
patient IS receiving a therapeutically adequate
amount of the drug at all times The elum-
nation of the maxima reduces the total
amount of the drug needed to obtain con-
tinuity of the desired response So much drug
may be wasted m the maxima that three con-
ventional 50 mg tablets can be replaced by
100 mg of the drug m a sustamed release
form With the sustamed release form no
drug IS wasted because the drug concentra-
tion docs not exceed, and is mamtamed at,
the level of the M E D
In addition to eliminating the peaks and
the dips in drug level inevitable with multi-
dose administration, sustamed release is a
convenience to the patient and the nursing
staff With a reduction m the number of doses
taken daily, the patient is more cooperative
and less likely to forget to take his medi-
cation
For case of iliscussion, susiaineti release
preparations are usually classified according
to their method of preparation From the
viewpoint of the physician and the pharma-
cist who IS advising the phywaan concerning
sustamed release products, a classification
based on Uie type of release is most valuable
The type of contmuous release from a sus-
tained release dosage form is release or solu-
tion of the drug in a steady, uninterrupted
manner from tlic mitial to the final amount
of the drug released An ideal sustained-
Susfained Release Pharmaceuticals
141
release product \^ouId provide continuous
release of its medication The erosion, the
lon-exchange resin and the leaching pharma
ceutical technics yield products with this type
of release
Incremental release is that type of release
which IS not a steady release rather the drug
IS released or dissolved m parts with a fixed
time interval (durmg which no drug is re
leased) between each part released The con
trolled dismtegration type of sustained release
provides incremental release
Methods of Obtaining Sustained
Release
Sustained release may be obtained by
pharmaceutical, chemical and biologic meth
ods Medical or biologic means are limited
to the immediate use of the physician and are
of little significance to the pharmacist
PHARMACEUTICAL TECHNICS
Controlled Disintegration The method
first used for controlling the release of a drug
was the entenc coating The disintegration
of the entenc coatmg is based on pH of the
gastrointestinal tract, chemical and enaymatic
action within the gastrointestinal tract, or
the time m contact with moisture The most
reliable release is that based on the tune m
contact with moisture Although an entenc
coating releases the medication u\ the intcsr-
tine or after an average time of 6 hours, it
IS only a controlled and not a sustained
release dosage form
Repeat action tablets consist of a tablet
withm a tablet or a laminated tablet in which
the outer shell or a layer disintegrates rapidly,
releasing the initial dose for immediate edcct
The core is entenc coated with shellac or
some resistant coating which protects the
core from fluids for approximately 4 hours,
after which the core disintegrates relcasmg
a second dose of the medication The core
may be press coated or pan coated with the
drug to be released mitially
Repeat action tablets are also known as
delayed action and timed release tablets A
repeat action tablet liberates the drug in an
amount that exceeds the immediate need, and
the drug lc\cl drops sharply after mgcstioa
The drug Ic\ el falls below the M E D before
Fio 60 Repeat action tablets with a
pan-coated or a press-coated shell which
releases drug for immediate use and a core
which does not release any drug for sev
eral hours
the core disintegrates When the core dis
integrates there is again a drug concentra-
tion similar to that from the first dose
Usually, these 2 stages do not overlap, so ^at
there is no therapeutic advantage with repeat-
action tablets The advantage of repeat-
action tablets lies in their usefulness to the
patient who needs medication during the
lours of sleep
126 B
Tnanunic (Dorsey) 12
Sig One swallow ed whole in morning
127 U
Demazin Repetabs (Schenng) 24
Sig 2 morning and evening
128 »
Prestabs Boliserpine R A
(McNeil) 30
Sig One daily
129 1}
Bcntyl Repeat Action (Merrell) 60
Sig Onet 1 d
130 1}
Coavertin (Aseber) 30
Sig Two with meals
131 n
Bcotril Timed Tablets No 1
(Carnnek) 50
Sig. One before breakfast
142 Solid Dosoge Form*
Fig 61 (Aboie) Pellet type sustained
release illustrated by a Mcdule capsule
(Below) Left the immediate action pci
lets from a Spansulc Right the sustained
release pellets from the same capsule
A pIuraLty of coatings applied to pcUei$
has successfully approached ideal sustained
release Spaosme is the best known example
of sustamed release uhich depends on d(f.
ferent thicknesses of the coating on many
pellets to produce various disintcgratioQ
tunes
Spansule consists of a capsule containing
a large number of pellets coated with various
thicimesses of a slowly dispersible substance
as well as lucoatcd pellets or powdered drug
to provide initial dnig concentration Eadt
group of the coated pellets, usually 100 per
group, contains an equal amount of the drug.
The total amount of drug m the sustained
form IS from 2 to 4 tunes the dose given m
a conv cntiooal tablet or capsule
Any desired release can be obtained by n
plurality of coatmgs but, usually, 3 coated
groups arc employed If X represents the
thiclmcss of a coating which releases the
drug at the end of 9 hours and Y is the num-
ber of coated groups, the thickness of the
coat for the first group is X/V, and the thick-
ness of the coat for the second coated group
IS 2X/Y In actual producuon, the coatmg
ranges from 30 to 40 per cent on either side
of the median coating. A good approxuna-
tion may be based on the weight of the coat-
ing where X represents the weight of the
median coatmg of the group which dismtc-
grates last
The nucleus of each pellet is either a 12-
mesh to 40-mcsb nonpareil or the drug and
sucrose made into a pellet The nonpareils
arc coated with syrup and the drug, employ-
ing conscntional pan coating technics Re-
peated coals of the drug arc added to the
nonpareils until by assay the proper wei^t
of drug has been built up on the sugar pel-
lets These are the uncoated pellets wfcch
release the drug for immediate effect
Three fourths of the imcoatcd pellets arc
pan-coated by spraymg a warm solution of
glyceryl monostcarate and beeswax m carbon
tetrachloride onto the pellets rotating m a
coatmg pan Other watcr-msoluble, mdigesti
ble lipids such as paraffin, camauba wax,
baybeny wax or cholesterol may be used to
sbw disintegration of the coatmg Other
watcr-dispcrsiblc or digestible substances
may be used such as the higher fatty alco-
hols, stcanc acid, diglycol stearate and esters
of fatty acids of high molecular weight
Two thirds of the thinly coated pellets ore
further coated by the same process These
form the second coated group of pellets cov-
ered with a film of mtenncdiate thickness
and having an intermediate dismiegration
time
Half of the pellets, which are coated with
the film having an intermediate dismiegra-
tion time, are coated further to form a third
group of coated pellets which dismtcgratc at
9 hours
Ejch of the 3 groups of coslcd pc^eis and
the group of uncoated pellets eaeffi contams
the same weight of the drug The 4 groups
of pellets arc blended and encapsulated.
If all of the pellets m each coated group
were covered with a uniformly thick coat
the medication would be released after the
iniual release m 3 discontmuous surges In
actual production, there is some vanaiion of
thickness of the coat within each coated
group The variance of thickness withm each
group permits some pellets to dismtcgratc
sooner than those with the median thickness
of that group The drug so released overlaps
the drug rcmaimng from the previous group
Some pellets wtthm a group ore slightly
thicker than the median thickness and do not
dismtcgratc until later so that the drug re-
leased overlaps with the next group Hus
Sustained Release Pharmaceuticals 143
overlapping between groups provides a
smoother and more uniform release which
approaches a contmuous type of release
Spansules dismtegrate mdependent of pH
with the release mechanism pnmarily one
of moisture vapor pressure permeability of
the hpid film. The drug, the composition of
the coatmg and the thickness of coating
deteimme the rate of moisture permeahihty
In addition to promoting a sustamed re*
lease effect, Spansules provide a more uni-
form distnbution of the drug m the gas-
tromtestmal tract If a smgle tablet fails to
disintegrate, the benefit of the entire dose is
lost If a few pellets of a Spansule fail to dis-
mtegrate, the loss of a small amount of the
total drug will not greatly affect the over-all
dose
Fundamentally, Medules function sinulariy
to Spansules The pellets are of uniform size
so that no stratification occurs during the
encapsulation process The release of the
medication is dependent on the composition
and the thickness of the coating The coat
consists of a styrene-maleic acid copolymer
which IS pH'Seosiuve and prevents dissolu-
tion in the stomach acid
Shellac coatings may be added in sufficient
number to provide delayed disintegration
time of nonpareils which have been coated
with active mgredients These pellets are
blended with a conventional granulation and
compressed mto a tablet Pellets coated with
ethyl cellulose are elastic enough so that they
can be compressed with a conventional gran-
ulation wthout rupturing the coating during
compression
A sustained-release tablet may be made
by compressmg a tablet from a blend of a
conventional granulation and a sustained-
release granulation The sustained release
granulation consists of the drug coated or
granulated with zem, cellulose acetate or
ethyl cellulose Other sustained-release granu-
lations consist of the drug held in a slowly
dispersible or digestible matnx of glyceryl
esters muted with fatty acids and alcohols
The uaxy ingredients may compose 25 per
cent of the delayed tunc material
132 n
Tuss Ornade Spansule (SKF) 12
Sig One daily
Fig 62 {Left) A cooventional granu-
lation IS compressed with a sustained-
release granulation {Right) Sustained-
release pellets are compressed withm a
conventional granulation
133 n
Medrol Medules (Upjohn) 60
Sig One in morning and evenmg
134 n
Nitroglyon (Key) 50
Sig One before breakfast and h s
135 B
Bellergal Spacctabs (Sandoz) 50
Sig One morning and evenmg
136 B
Pentrilol Tempules (Armour) 45
Sig OaeA.M&pM
137 B
Timed Amodex Capsules (Test
agar) 30
Sig One on arising
Erosion. In the erosion techmc of obtam-
ing sustamed release an insoluble tablet is
formed which contmuously releases the drug
due to the unmterrupted surface erosion of
the tablet and the solution of the drug The
tablet does not dismtegrate and maintains its
geometric shape as it passes through the gas-
trointestmal tract Because the geometne
shape IS unchanged while the tablet erodes,
them IS a continual decrease m the weight
of drug released per unit time as the surface
area of the tablet is progressively reduced.
The erosion technic is generally used with
a press-coated or a pan-coated outer shell
144 Solid Dosage Forms
Fto 63 Urosion type susiamcd release
tablets {Abo\e) Tablet cores arc press
coated with a shell to proside immediate
drug release (Z^uer nghl) The tablet is
a laminated tablet with an immediate re*
lease and a sustained release layer
which ts applied in the contcniioaal manner
to the specially formulated core After ad-
ministration, the shell disintegrates rapidly,
providing an immediate concentration of the
drug The core then begins to erode at a
rate determmed by the proper blend of a
waxy tablet base and the drug No shellac or
enteric matenals arc used in this method
The drug is suspended in a solid fat or a wax
of high molecular weight As the tablet
erodes, the drug is continuously dissolved
and IS available for absorption
Industrially, the drug and the melted fats
and waxes are blended in a thcrmoslatcd
mixer with milling and sweeping blades to
maintain a uniform liquid suspension The
uniform suspension is passed through a
stcam-]ack.ctcd valve onto a cooling (^m
The congealed blend ts sinpped from the
drum and ground at low temperature The
resulting granulation is compressed mto a
tablet and press-coated if desired
The continuous release of the medication
and the elimination of the waste of drug at
the maxima obtained with conventional tab-
lets reduce the total drug necessary to main-
tain a therapeutic response One Lontab
containing 100 mg of pynbenzamine ts ther-
apeutically cquiv^cnt to 3 conventional 50
mg tablets
Two or 3 separate granulations may be
pressed together to form a multiple-layer
tablet One layer contains the drug readily
available for immediate use Another layer
— the sustained-release layer — is compressed
and formulated so that it will retain its shape
during Its passage through the gastrointestinal
tract If the layer is cylmdricd with a large
diameter compared with the height of the
layer, the eroding or dissolving surface will
remain essentially constant A constant sur-
face means that tlic drug will dissolve and
be released at a constant rate, more nearly
meeting the requirements for an ideal sus-
tained release dosage form
The erosion or the gradual flak.mg oH of
the surface is based on an atuiuon, and it
IS independent of pH
138 n
Preludm EndurcU (Gcigy) 30
Sig * One tablet m imdmoming
139 »
Doanaul Extentabs (Robins) 30
5ig One morning and nighL
140 n
Sul-Spaniab (SKF) 75
Sig 4 at start, then 2 doily
141 n
Pentraie Sustained Accioa
(Wamcr-ChilcoU) 50
Sig Oncq I2hn
142 n
Pen-VccL-A (Wyclh) 12
Sig Two daily
Ammophyllm Dura-Tabs (Wynn) 18
Sig 1-2 tablets every 12 hn
144 «
Kovahistioc Singlet (Pitman-
Moore) 12
Sig One q 8 hrs
145 U
Mcstinon Timespan (Roche) 25
Sig . Two bid
Leaching is the process by which there is
steady dissolution and removal of a drug
from on insoluble, intact matrix. One may
consider the tablet as an mert sponge wiib
Susloined Release Pharmaceuticals 145
its pores filled with the drug The mtact
matrix of Gradumets consists of a copolymer
of methyl acrylate and methyl methacrylate
which passes unchanged through the gastro-
mtestinal tract and is eliminated in the feces
The Gradumet is produced by oompressmg
a granulation of the drug with the insoluble
plastic material
When the tablet reaches the stomach, some
of the drug m the superficial channels is
leached out rapidly to provide an immediate
therapeutic effect As the tablet travels along
the mtestme, the drug is leached out from
the deeper channels or pores over a pro-
longed penod The release of the drug is inde-
pendent of pH and enzyme concentration
Control of drug release is obtained by
varymg the porosity and the ratio between
the exposed surface of the plastic matrix and
the dissolving drug If the drug is spanogly
soluble, a highly soluble substance may be
added to facilitate dissolution from the <^an-
nels Such a soluble substance is known as a
channeling agent
146 9
Nembutal Gradumets (Abbott) IS
Sig One on arising
147 3
Metamme Sustained (Leemmg) 50
Sig One every 12 hours
Ion Exchange Resin. Ion exchange is the
process by which an insoluble resin extracts
ions of one land from solution and exchanges
them for ions of another kmd onginaUy
bonded to the resin The formation and the
dissociation of complexes utilizing organic
acids or bases and certam ion exchange resins
proceeds at a fimte rate It is claimed that
when the ion exchange resin is chosen prop-
erly, the rate of dissolution will produce
uniform drug release dependent only on the
concentration of ions available in the gastro-
intestinal tract
The lesmate is insoluble and releases the
drug by double decomposition in which the
drug IS exchanged for on ion Cationic ex-
change resins are used to replace a specie of
cation with another specie of cation The
resins used for sustamed release are cationic
exchange resms combined with a cationic
form of the drug to be released.
Fig 64 {Left) A Gradumet tablet
(ffigAt) One which has been exposed to
water for 24 hours
SOjO (Drug) SOjONa
-fNaCl-i. |^+(Dnig)+a-
-CH-CHa- -CH-4:H2-
The drug is released by an exchange with
the cations found in the gastromtestmal ff uids
The rate of release is said to depend only on
(he total concentration of these cations Since
this wncenlration is nearly constant through-
out the entire gastrointestinal tract, the re-
lease 1 $ claimed to be predictable, continuous
and controlled
The bead size of the lesm affects the rate
of release of the adsorbed drug With a small
particle size, the drug is released more
rapidly A 200 mesh bead has a greater sur-
face area per unit weight than a 20-mesh
bead With a greater surface area the drug
IS eluted or exchanged faster and will not
give as prolonged an effect as the larger
bead The degree of cross-lmkage of the
resm and the quantity of drug removed from
the particles during elution ^ect the rate of
release
Durabond products consist of drugs con-
taining on amine group complexed with tan-
nic acid This large molecular polyionic com-
plex IS claimed to release the drug gradually
and uniformly The complex salts are pre-
pared by reacting on alcoholic solution of
(he therapeutically active amine with a 20
per cent excess of tannic acid. The reaction
mixture is diluted with ice water to complete
the precipitation The precipitated tannatc is
collected and dried
The tannatc complex is insoluble, but, in
(he presence of electrolytes and with a lower-
146 Solid Dosage Forms
HOURS
Fio 65 Fraction of the drug released
from sustained release dosage plotted
against time The fraction t, is released
immediately to provide the miUol activity
(Wiegand R G and Taylor, J D Drug
Standards 27 165 1959)
mg of pH, there is an increased release of
the amme The rate of release is often rc»
tarded by the addition of polygalacturonic
aad
148 H
lononuD 30 (Strosenburgh) 30
Sig One fO 14 hrs before rciinng
149 n
StimaJose Durabond (Irwm
Ncisler) 50
Sig One daily before breakfast
aiEMlCAL TEaiNlCS
A biologically acme compound may be
modified chemically to form an inactive dc>
mauve tshich liberates the parent compound
on exposure to cn^mauc action m vivo
With such roodificauoo. there is at tunes
modified absorption of the drug from the
gastromtcsimal tract.
To overcome the bitterness of chloram'
S ' :aicol, the palmitaic ester is prepared
e insoluble and tasteless chlonunphcnicol
palmitatc is administered to persons who
cannot swallow a capsule and to children as
a Qavored suspension The palmitatc ester
has very little antibiotic activity, but it under*
goes hjdrolysts in the gastrointestinal tract
where it is converted into Uic acUve alcohol
A somewhat prolonged action results be-
cause, a$ the chloramphenicol palmitatc
passes along the gastromtcstmal tract, there
is a conUnuous hydrolysis and absorption of
the active drug until the palmitatc remaining
is excreted m the feces A dose of the pal-
mitate equivalent to 500 mg of chloram
phcaicol IS detectable in the blood for 12
hours
An acuve substance may be modified
chemically so that its absorption, distribu-
tion or metabolism is altered, but the type of
response is uocliangcd The length of time
for which lidocainc exerts its anesthetic effect
probably depends on the tunc required to
hydrolyze the amide linkage m the body If
the two methyl radicals m lidocaine arc re-
placed by hydrogen atoms, the resulting com
pound 1 $ rapidly hydrolyzed and exerts its
effect for a shorter penod Compared with
this compound lidocamc has a more pro-
longed clicct, as the two methyl groups
stencally hinder hydrolysis
MEDICAL TCCIiNICS
A prolonged effect is obtained by the ad
ministration of a second drug which will slow
the excretion of the pnmary drug and pro-
long Its action Oral penicillin is rapidly ex-
creted by the kidney The effect of pemeifiin
IS prolonged by the administrauon of pro-
benecid which interferes with the renal ex-
cretion of pcniciUxa, so that it is not readily
excreted As penicillin remains m the body
longer, Its action is extended
^rtain drugs arc very lipoid soluble and
arc partitioned and deposited m the adipose
tissue The drug deposited m the fat estab-
lishes an equilibrium with other body com-
partments and It IS gradually released to pro-
vadc a prolonged effect Chlorotnamscoc is a
long acting estrogen because of this phe-
nomenon
A prolonged effect may be obtained from
the effect of a second drug which modifies a
physiologic enoyme system responsible for
ibe inacijvaljon of the ptunary drug Acetyl-
Sustained Release Pharmaceuticals
147
cholme is hydrolyzed or inactivated by cho-
linesterase Neostigmine combmes wiUi and
inactivates cholmesterase, thus prolongmg the
activity of acetylcholine as there is less en-
jtyrae available to hydrolyze the acetylcholine
Medical technics have limited application
and are restncted to direct use by the phy-
sician The secondary drug often has undesir-
able actions m addition to its prolongation
effect At times a massive dose is required to
obtam the prolonged effect, and it would m-
volve less risk to the patient to use a conven-
tional dose regimen
Limitations or Sustained Release
Marketed preparations do not release a
drug with a constant release per umt tune
but exhibit a continuously decreasing release
with tune The rate of release becomes pro-
gressively less than the rate of elimuiation
Ideally, a sustamed-rclease dosage form
should release the drug at a rate equal to the
rate of disappearance from the body The
products marketed provide a release of the
drug at a rate which appreciably increases
the length of activity They are prolonged-
release preparations
For sustained release preparations of dif
ferent mechanism and form, the pattern of
release of various drugs is approximated by
a first-order equation For many preparations
the rate of release of the drug from the sus-
tained release form is proportional to the
amount of drug remaining.
or m the integrated form.
log — =
kt
23
( 2 )
where a, is the total dose of die drug m the
product, a is the fraction of the to& dose
remaimng m the sustained-release prepara-
tion at tunc t if a« is unity, and k is the
apparent specific release constanL
With a sustained release dosage form
which releases a fraction of the dose (f|)
immediately and another fraction (f«) ex-
ponentially, the amount of the drug released
(ar) atony time is
a, = a,f, + a,f, (1 - e-«)
HOURS
Fic 66 The logarithm of the fraction
of drug in the sustained release solid dos-
age form IS a linear function of tune
(Wiegand, R, G , and Taylor, J D Drug
Sundards27 165, 1959)
Obviously, if all of the drug is released,
fi + fi = I With the ion exchange mecha-
nism of sustained release, fi + f, is less than
1, mdicaliDg that all of the drug is not re-
leased
In piomoUonai iileraiure the release curve
IS often presented as a plot of the cumulative
fracUon of the drug released against tune as
shown m Figure 65 Smee the amount of drug
released at a particular tune is of more sig-
nificance, a better understandmg of the drug
bemg released at different tunes is obtamed
by a plot of the logarithm of the amount re-
maming to be released as a function of tune
as shown ui Figure 66 With 100 per cent
release the intercept on the ordinate is the
logarithm (f«) and k equals the slope multi-
plied by 2 303
Sustomed-release products of the leach-
ing and the lon-exchange types release their
drag most closely m accord with equation 3
This IS to be expected, as the diffusional
processes of release from an mert matrix and
the ion-exchange mechanism are both first-
(3)
148 Solid Dosage Forms
onlcf processes With the erosion type ttiUet,
as the surface area decreases the rate of re-
lease decreases Thus, this t)pc of sustaiaed
release may be descrilTcd by equation 3
Release from a multiple pellet sustamed-
rclcasc product approximates a first order
release. This of preparation probably
has the capability of any desired release pat-
tern through the mcorporauon of pellets with
the proper distnbution of coating ^icinesses
A slight deviation from a first-order pattern
IS not unexpected, in view of the diiTerent
form and mechanism of release, however,
the release is suflicicntly precise to warrant
the use of equation 3
Sustamed release products of all types ex-
cept the lon-cxchange type release part of
their drug for immediate use Since the res-
irute form releases no drug immediately, the
term aJi is zero, and the curve passes ihrou^
the ongin when the cumulative amount of
the drug released is plotted as a function of
time
Preparations to be administered occasion-
ally should have a fi value suQlcicnt to pro-
duce a rapid ciTcct The value depends on
the dose incorporated m the preparation and
the dose of the specific drug For products
designed for repeated admuustratioo, f|
should be as close (o zero os possible, smcc
the drug level is not starting from zero after
the first administration This eliminates one
source of maxima and troughs m the levels
of the drug ui the body
In Vitro cxpcnmcnis have borne out the
above relationship which has been correlated
with in vivo urinary excretion patterns of
many drugs
As most drugs arc absorbed m the upper
mtcsimc to a greater extent than m the lower
intestine, the dose or the amount of drug re-
leased after 7 or 8 hours should be greater
than the drug released at 4 or 5 hours to
compensate for the decreased absorption
The opposite release is obtained from most
marketed products
Althou^ sustained release medication is
advantageous, there arc limitations in its use
When a precise dose is essential, such as
with the digitalis glycosides, sustained release
probably should not be used m view of the
possibility that physiologic variance may alter
the normal release pattern and fad to provide
the critical dose required.
Physiologic variance makes it difficult to
achieve the ideal pattern of sustamed release
This IS not a major consideration watli a
normal mdividual, however, with persons
known to have impaired or erratic gastro-
mtcstmal absorption, sustained release mcdi-
cmion should not be used
Commonly, there is 3 to 4 times the
amount of drug in a sustained dosage form
as there is in a conventional one If die dos-
age form should be used improperly, sucii
as by chewing an erosion typo tablet instead
of swallowing the whole tablet, the patient
would receive an overdose For this reason,
a drug should not be placed in a sustained-
release form unless the margm of safety is
substantia]
Pharmaceutically, a drug with a large dose
IS difficult to develop into a sustamed release
form The bulk resulting from the drug and
the excipients which control the release is
too great to produce a tablet or a capsule
that can be eas Jy swallow cd
Drugs such as digitalis, isopropamide, phe-
noborbital and sulfamethoxypyridazme nave
a long biologic half life and usually require
only a single daily dose With inherently long-
acting drugs there is no need for addiuonal
treatment to prolong their effect
Therapeutically, it is not always advan-
tageous to employ sustamed release medica-
tion Sustamed release multivitaimns appear
to be unnecessary, no beneficial prolonged
effect has been demonstrated with riboflavin,
ascorbic acid or thiamine Admmistration of
anticholinergic drugs to persons who arc
anticholmcrgic sensitive may produce side
effects, os by altering the gastrointestinal mo-
tility and secretions, the absorption of the
drug IS affected Cases of angma of effort
should not be treated orally with sustained
action nitriles The prolonged effect may ob-
scure the warning signs of pam and lead to
ovcrcxcrtion with fai^ results
Evaluatjon of Sustained Release
No single m vitro test will adequately
reflect the availability of a drug from a sus
lamed release mcdicauon The USJ* dis-
inicgrauon test docs not apply to sustained-
release dosage forms, smcc the amount
released per unit time is the cntical factor
to be evaluated
In view of the several mechanisms by
Sustained Release Pharmaceuticals 14^
which sustained release is accomplished, it
IS doubtful that a smgle standardized me-
chanical unit and elution fluid will prove
satisfactory It seems more hkely that a me-
chanical means of testmg the release may be
developed for each mechanism of release
after correlation with climcal release patterns
In-vitro release tests for sustamed-release
products are meaningless unless correlated
with m-vivo measurements After the vabd-
rty of a sustained-release product has been
demonstrated by m-vivo testmg, m-vitro
measurements may be correlated and used
for production control
In vivo evaluation of sustamed release
dosage forms m humans is earned out mainly
by detenmnations of blood level and urine
level and by sub]ective clmical evaluation
The determmation of blood levels affords a
way of estimating the ume of onset and the
duiauon o! effect for a drug if the M E 0
and the maxunum blood level concentrations
have been determined Blood levels have been
used with prednisolone, pemcillm, oxytetra-
cyclme, sulfaethylthiadiazole and caffeine
Some drugs are used in concentrations so
low that they cannot be quantitatively de-
tected m body fluids Measurement of activ
ity IS then a subjective and a somewhat ob-
scure evaluation
Unnaiy excretion methods offer a means
of measuring the drug absorbed provided that
the drug is excreted unchanged or the me-
Vabotam of the drug is xmderstood For such
drugs there is a direct relationship between
excretion rate and the amount of drug m the
blood Smcc the clinical response of many
dmgs parallels their conccnlralion m the
blood, a valid relationship exists between the
therapeutic effect and the amount excreted
m the urme If a dosage form is found to have
prolonged unne levels, it would have pro-
longed clmical effect Amphetamine, aspinn,
pemciUm, sulfaethylthiadiazole, tetracjclme,
nicotmic alcohols, tnmeprazme, phenylpro-
panolamme and riboflavin have been studied
by the unnary excretion techmc
Toxicity tests m animals have been used
to evaluate lon-exchange resins To use a
toxicity techmc, one must have a drug wifli
a relativity high toxicity In comparing the
LD50 of the untreated drug with an lon-
exchange resmate, the lethal dose is raised
and the time until death is longer with the
resmate than with the untreated drug Similar
experiments show that the larger beads of
the resmate have a higher lethal dose and a
longer lime until death than small resmate
beads Toxicity studies are valuable m the
development of a product, however, ±cy give
00 mdication of the physiologic availability
of the drug
In VIVO roentgenogiapbc techmc has been
widely used to study the release from en-
capsulated slow-release pellets This has
proved that there is a wide dispersion of the
peUets after 1 hour 10 the gastromtestmal
tract
Radioactive isotopes have been used as
tracers m anunal studies The availability of
radioactive drugs has been the restnetmg
factor m the application of this technic
The final evaluation of sustamed action
products must be done by property designed
clmical tests with humans The actual meas-
urement of drug concentration or activity re-
sultmg from a smgle dose and multiple doses
must be compared with that of the sustained-
release dosage form
C/iopfer 4
Solution Dosage Forms
Jere E. Goyon, B S., Ph D.*
A solution may be defined as a homoge-
neous liquid consisting of at least two com-
ponents The student will realize that this
dffSnjlJca encompasses a Ja/ge number of
diilcrcnt dosage forms familiar from earlier
studies Thus, ue wish to emphasize the
sumlantics betsNcen products suen as syrups,
elixirs and tinctures, rather than their dif-
ferences
Solution dosage forms base some impor-
tant advantages drugs must dissolve to be
absorbed and thereby be effective, many pa-
tients (especially children) cannot swallow
tablets or capsules, and uniformity of dosage
IS easily obtainable However, they do have
some disadvantages they are liable to un-
dergo detenoration and loss of potency, they
present many flavormg problems, and many
mcompatibilitics arise due to mtcractioos be-
tween dissolved species and to changes in
solubility produced by solvent alterations
In oi^er to mix various dosage forms m-
tcUigcntly the pharmacist must always be
aware of the solvents which arc used in the
original liquids Thus, changes m alcohol
concentration due to mixing an elixir and a
syrup will explain the ensumg solubility
problems
The need for several solvents having dif-
ferent properties may be readily understood
by considcrauon of the dissolution process
SOLUBILITY
TiiE DissoLimos pROCCSSf
In order to discuss solutions, the sub-
* Associate Professor of Pharmacy, The Uai-
scrsiiy of Michigan College of Pharmacy, Ann
Arbor
t This Ueotmeal ii not intcoJcJ to be a rigorous
Uevclopmest of the subject but rather to providfl
the uudeat with an insight into this very complex
field.
Stance present m largest amount w lU be desig-
nated the solvent, and other substances pres-
ent m lesser amounts the solutes The
qucsimn aatursUy arises' ca ^hich of the
three states of matter (gas, liquid or solid)
docs a dissolved solute exist? The molecules
of a dissolved solute do not occupy fixed
positions with regard to one another, thereby
ruling out the ciystallmc state Furthermore,
they do not uniformly occupy all volume
available m the cooiamiog vessel, thus ex-
cluding the gaseous state This leads to the
conclusion that a solute dissolved in a liquid
IS, Itself, m the Lquid state Therefore, the
dissolution process must contam a step for
converting any other state of the solute to
the Lquid state
After convcniOD to the liquid state, the
molecules of solute and solvent must be urn-
fonnly mixed This requires a step which
consists of overcoming the attractive (co-
hesive) forces between solute molecules (and
between solvent molecules) and replacing
them with new forces due to solvent-solute
mtcractioos Such disruption of forces m-
volvcs work (or energy) Ganges This energy
rearrangement is known os mterchange
energy and may be visualized as follows.
Consider two liquids A and B Assume mole-
cules A and B arc similar m size so that a
molecule of A will be surrounded by the same
number of molecules (m), whether m Lquid
A or B Now transfer one molecule of A to
liquid B with simultaneous transfer of a mole-
cule of B to liquid A. The work done or
interchange encr^ must then be.
AE = -ra(2w^B - Waa — Wbb)J (I)
If this is done with x molecules, the total
mterchange energy is x tunes aE, the total
t w,k = work Dcceuory to tcporxie two mole*
coles of A. w,a onJ w*t similarly
IdO
Solubility 151
energy change being designated as the heat
of mixing A negative aE corresponds to
the release of heat (exothermic process),
while a positive AE corresponds to absorp*
tion of heat (endothermic process) If the
diSerence m attraction is sufficiently great
(size differential may also play a part due to
changes m m) the two hqmds may not be
miscible Cases where the attractions are
exactly equal will produce no energy change
and will be considered as ideal solutions
Suipnsmgly, a good deal of information
about a solution may be obtamed by study-
ing the vapor above the solution Tlus may
be shown in the following manner
Consider the saturate vapor above pure
liquid A at temperature T The number of
molecules of A retummg to the liquid from
the vapor phase per second, i e , the rate of
condensation, is proportional to the vapor
pressure of A (P^a) and the area between
the liquid and vapor (S) ITus may be ex-
pressed as
Ro = ki P^S (2)
where kj is the constant of ptoporlionahiy
The rate of molecules leaving the hquid by
evaporation will be proportional to S
Re = ksS (3)
At cquilibnum the rate of condensation must
be equal to the rate of evaporation, leading
to the following expression for the two con-
stants of proportionality
= (4)
Now assume B dissolved m A In a nus-
able solution the condensation proportion-
ality constant will be unaffected, smce a
molecule of A may return at any pomt on
the surface
Ro = kxPxS (5)
where Pi is the pressure of A above the
solution Tlie rate of evaporation of A will
depend on the proportion of S which is oc-
cupied by A, which, m turn, is dependent on
the mole fraction of A, Xi * This may be
expressed as
Ra = k*XiS (6)
*The mole fractioa of a solute u tbe number
of moles of tbe solute divided by tbe total nun
ber of moles m tbe solution.
Agam, at equilibrium Re = Rc, and using
equation (4) vve oblam
Pi = -|- (7)
hi the case of an ideal solution the forces
between A-B are equal to those between A-A
and B-B, therefore ka = ks This results m
the Raoult’s Law equation
Pi = P«i Xi (8)
which may be used to define an ideal solu-
tion If the A-A mteractions are stronger
than the A B mteractions, k 2 <k 3 The vapor
pressure of A above the solution wiU then be
greater than that predicted by Raoult’s L^w
Thus, measurements of the vapor pressure
may be used to obtam an understanding of
the mteractions m the liquid state It should
also be noted that the boiling pomt of a
liquid IS a good measure of its cohesive
forces As the cohesive forces mcrease, kj
will decrease with no change m kj and the
boding pomt will therefore mcrease
The earlier discussion indicates that the
solubility of a sohd must depend on the
energy necessary to melt the solid, usually
referred to as the heat of fusion (^f) and
any beat of mixing The solubili^ of a gas
must depend on the beat of vaporization
(nHr) and the heat of mixing If the mter-
chaoge energy is zero, an ideal solution exists
and some simplifications are possible The
solubiii^ of a gas must decrease with increas-
ing temperaturet and the solubihty of a solid
must mcrease with mcreasmg temperature
The equation desenbing the solubility of
a solid which forms an ideal solution, as a
function of temperature is the usual van’t
Hoff type used m describing the effect of
temperature on equilibrium.
2 31ogX = ^l[^ J^^ ] (5)
where R is the gas constant (1 98 calories
per degyee per mole) , Tn is the melting point
m de^es Kelvm and X is the mole fraction
solubihty at temperature T Note that at the
melting pomt tbe solid is miscible with the
solvent (X approaches 1), as would be ex-
pected for an ideal solution This also pre-
dicts that the lower tbe meltmg point of a
t In order to effect tbe change in state (gas to
li(]ud) beat must be withdrawn from the gas.
’ TCyPEDATURC
l&0~ f
EMPCKATURE
Fio 67 Diagrams of the two poI)morphic systems a — mp of polymorph I, b = rap
of pol)cnorph II. t = transiuon potat.
solid the higher ils solubility * This can be
demonstrated by the solubility of fused ring
aromatic compounds m benzene (Table 19)
We may also compare a senes of closely
related substances (Table 20), since the lo*
tcrchangc energy should be similar tor each
The changes in solubility are coosequcotly
due to dilTcrcnces tn the melting point
The relationship of melting point and solu*
bility IS particularly interesting m the cose
of poKoiorphic substances t Polymoqihs are
crystal forms of the same substance having
diiTerent melting points (The student uiU
recall the different ctystal forms of sulfur as
an example ) Two distinctly different poly-
morphic systems arc possible They may ^
understood most readily by reference to Fig-
ure 67 The vapor pressures above the ciys-
lals and the liquid arc plotted vs the tem-
perature In port A me transiUon pomt
(temperature at which both fonns have the
same vapor pressure) is belowr the mclung
pomt of polymorph I, and the system is
cnantiotropic In part B the transition pomt
• Tbo tap. of A lubslAQce dcaeascA u tbe
puucle sire U reduced below about 2 nucroos
djAtseier aod ibe totubibiy ahowi a coscurreol
loaeue.
t Compue diKuuton Chapter 2, page 60
Table 19
Mole FMcnas
SoLUBiLmriN
CoM roUNp M P *C. DenzijiE
Naphthaleoe 80* 81 027
Pbeoaiiilbrcoe 99*100 0.21
Asthraceoe 217*218 OOOSl
IS above the mcllmg pomt of polymorph I,
and the system is monotropic
The heat of mixing must be the same for
all polymorphs The solubility wiU, of course,
always be greatest for the polymorph with
the bluest vapor pressure Thus, the solu-
bility of a monotropic system follows the
nile that the lower melting form will always
have the higher solubility EnanUotropic sys-
tems are more complex Figure 67 (left)
shows that the solubility of polymorph 11
vvxiuld be higher at 25^6. but polymorph I
would be more soluble at lOO^C
There is currently great interest in the
pharmaceutical industry m the mvestigation
of different polymorphs of slightly soluble
drugs*- Table 21 illustrates both types
of polymorphism
O/ course, the consideracion of solubility
10 nonidcal systems must take into account
the heax of mixing Tlus may readily be seen
Table 20
DABBtrURATE
MP ’C
SOLUDIUIY IM
Alcohol
Barbital
Phesobarbital
Amebaibital
Pentobarbital
Secobarbital
188*189
174-178
156*158
13M33
95- 96
1 Cm./14 ml
1 Gm./10 ml*
1 Gia/5 ml
I Gm /4 ml.
1 Cm./2 ml
SULfONAMZDB
MP
SouuBiLmr w
Water
Sulfadiazioe
^famcrazine
Sulfap}7idtne
Sul/ioUazole
252-256
234*238
191*193
173*175
1 GnL/13 L.
1 Gra./5 L.
1 Cm/3.51-
1 Gm./1.7 L.
Solubility 153
Table 21
Melung Point Solubility
Compound »C in Water
RiboSavia
Polymorph I 291-293 60 mg /liter
Polymorph II 283 1200mg./liter
Methylprcdnisolone
Polymorph I 205 0 075 mg /ml
Polymorph II >230 016 mg /ml
by noting that 1 Gm of phenobarbital is of mteracuons as those responsible for chem-
soluble m approximately 800 ml of water, ical bonding between atoms However, be-
700 mL of benzene, 40 ^ of chloroform, 15 cause of the larger distances over which they
ml of ether and 10 ml of ethanol are acting they are of considerably smaller
The over-all heat effect of the two-step magnitude The electrical nature is quite clear
process (fusion and mixmg) must be the in &e case of ions, where the force between
algebraic sum of the heats of fusion and mix- them is calculated from Coulomb’s Law
ing This sum may then be used m place of
tbe heat of fusion m equation 9 and a more f s 3 ^ ( 11 )
general equation useful for nomdeal solu-
tions obtained where q w the charge on each ion, D is the
^ AHf T T 1 dielectric constant of the medium between
(10) the ions and r is tbe distance between the
Sx R L ‘ a J ions Two other properties of molecules which
where Sa is the molar solubility at Ta, and result m elecincm mteracuons are permanent
Si at Ti Therefore, the determination of tbe dipole moments and polanzabihty The stu-
solubility at two different temperatures will dent w’lU recall that molecules in which the
tnakfl It possible to riafemiine aH This cqua- poslUve and the negative centers do not co-
iion then may be used to predict solubihues mcide are known as dipolar molecules The
at other temperatures product of the charges multiplied by the dis-
Now, It would appear from the previous tance between them is known as ^e dipole
discussions that the forces between pbeno- moment. PolanzabUity (usually designated as
baibital molecules are more closely related a) is a measure of the ease with which the
to those between alcohol molecules than to average electron distnbutton m a molecule
those between the molecules of any of the may be altered by an electric field This alter-
other solvents This is indeed the basis for tbe ation leads to an induced dipole moment m
rule of thumb that “bke dissolves like” It the molecule.
only remains, then, to define what is like It is now possible to list the various mter-
what action forces usually found in solute solvent
systems (Table 22)
Interaction Forces Xhe first four cases are easily seen to be
All mteraction forces are fundamentally electncal interactions and the forces may be
electneal m nature They are the same Qrpe predicted with the aid of Coulomb’s Lnw
Table 22
iNTERACnOV
Interaction Forces
Between Molecules
Interaction Energy
Pkoportiosal to
lon-dipole
r-*
Dipole-djpole
(Keesom Forces)
r-»
Ion induced dipole
r~*
Dipole induced dipole
(Debye Forces)
r-*
Induced dipole induced dipole
(London Forces)
x~*
154 Solution Dotago Forms
Table 23
Solvent
BP
axIO-i
m(«C)
D(“C.)
Diethyl ether
35
88
I 35(25)
4 3(20)
Acetone
37
64
1 36(20)
21(25)
Chloroform
61
84
1 44(20)
4 8(20)
Carbon tetrachloride
76
104
I 46(20)
2 2(20)
79
50
1 36(20)
21(20)
Benzene
SO
100
1 50(20)
23(20)
Water
100
14
1 33(20)
80(20)
Propylene clycol
189
76
143(27)
32(20)
Liquid petrolatum
-200
> too
I 48(20)
2 5(20)
Formamidc
210
42
1 45(20)
109(20)
Glycerol
290
80
1 47(20)
43(25)
The Joit ease u more Jtiheuit but may be
visualized as follovr's If ^^'e could take an
instantaneous snapshot of the electron dis*
tnbutioQ of a molecule, the molecule would
have a dipole moment (averaged over time
no dipole exists) This rapidly varying dipole
wilt then induce a dipole m neighboring mole-
cules in phase with itself These interactions
result in on over-all attractive force Such
forces east between all molecules but arc
only important when stronger forces arc not
present to mask tlicm Tlic polanzabduy of
a molecule is equal to the sum of the polariza-
bilities of Its constituent atoms London
forces will consei^ueaily increase with mo-
lecular weight. Dutance between molecules
IS also very important, and large Oat mole-
cules which may approach each other closely
(e.g , benzene) wm be more strongly at-
tracted than molecules which arc stciically
prevented from close association The sura
of the polarizability and the pcnnancot di-
pole moment may be measured by means
of the dielectric constant The dielectric con-
stant of a liquid may be defined by Coulomb s
Law (see equation 11) or as the ratio
of the capacitance of a capacitor with the
liquid as the diclcctnc to the capacitance
of the same capacitor with air as the dielec-
tric The permanent and the induced dipoles
align themselves oppositely to the applied
field, thus decreasing the electric field strength
and mcreasmg the capacitance As the fre-
quency of the applicu Geld is increased the
permanent dipole molecules find it increas-
ingly difficult to align themselves in opposi-
tion to the applied field Light may be con-
sidered a very high frequency clcctnc field.
Whea light passes through a polarizable
liquid Its velocity is less than its vcloaty m
air The relative velocity is defined as the
refractive index of the liquid (m) Therefore,
the refractive index of a liquid is dependent
on the polarizability, increasing as the polar-
izability increases *
Several properties of common pharmaceu-
ucal solvents arc given m Table 23
The coniribuuon of polarizability to the
dielectric constant may oc shown to be the
square of the rcfracuvc index Thus, for
substances bke benzene the diclcctnc con-
stant IS due almost cnutely to polarizability
1(1 S)‘ = 2 25] and the molecular interac-
tions arc due almost exclusively to London
foracs On the other hand, water with lU
high dielectric constant and low refractive
index must consist mainly of dipolc-dipole
interactions Water actually contams a spe-
cial subclass of Kccsom forces known as hy-
drogen bonds These differ from ordinary
Kccsom forces in that the small size of the
hydrogen atom makes the positive charge
more readily available (r will be smaller than
m other eases) and thus leads to stronger
bonding Any organic molecule contaming
N, O or other electronegative atoms will
therefore be capable of dipolc-dipoIc inter
actions If the electronegative atom is at-
tached to hydrogen, hydrogen bonding will
occur These conditions are quite common in
organic mcdicinals, and, therefore, Kccsom
•Tlio Brtual c<iuaUoo for pobiUabllity li
« = ”6 X M W
U tbfi moteculsr weight sad p the dcouty of the
L«|uiiL
Solubi]iVy 155
Table 24*
ADC
Solubility
G m /lOO ml
Propylene
Glycol
Glycerol
Alcohol
Water QS ad
71 1
022
0
0
15
100
70 4
0 22
20
0
0
100
704
0 22
0
10
10
100
65 2
0 22
0
40
0
100
62 3
044
0
0
30
100
645
044
20
0
10
100
63 2
044
35
0
0
100
62 6
044
0
15
20
100
59 3
044
0
40
10
100
* Modified from Kraiise G M and Cross J M J Am Pbarm Assoc Sci Ed 40 137, Peterson
C F , and Hopponen, R. E. J Am Pbarm Assoc 42 540
forces will play a large role m solubility phe-
nomeoa of such drugs
We are now m a position to answer the
earlier question what is like what? The an
s\ser is that liquids with similar interaction
forces are “like” one another Water and
benzene have similar boiling points and must
therefore have approximately equal cohesive
forces However, the cohesive forces in water
are primarily of the Keesom type and those
in benzene, of the London tjpe The mter-
action forces ( A-B of our former discussion)
will be small (a£ a large positive number),
preventing miscibility of these liquids
Ioa*dipole interactions are particularly
teresUng, the most important examples being
salts m water The interactions of tons with
water dipoles are strong enough to overcome,
m many cases, the adverse eoect of the high
melting point of the sdt However, it must
not be assumed that all salts are highly water
soluble In many cases (obvious examples
are silver chlonde and quinine sulfate), the
hydration energy is not sufficient to over-
come the heat of fusion and solubihty is
therefore quite low
However, the formation of a charged spe-
cies from an uncharged species docs lead to
an increase in Vfater solubility Quinine sul-
fate IS considerably more soluble than the
free alkaloid, even though it has only slight
water solubdity This principle may be used
to enhance the water solubility of poorly
soluble alcohols The^coholisestenfi^with
a dibasic or tnbasic acid and the mono ester
formed is made into a salt by the addition
of sodium hydroxide The final product ts
considerably more soluble than the parent
molecule and often has good pharmacologic
activity Riboflavm phosphate (water solu-
bility 100 X r^boflavm) IS a good example
An especially important example of salt
insolubility occurs when both amon and
cation are large organic molecules la this
case the strong interactions between the ions
and the water dipoles are markedly decreased,
causing a concurrenl decrease m water solu-
bflity This situation commonly occurs when
large cation*eontainmg molecules such as
benzalkoniuro chlonde and large amon-con-
tainmg molecules such as sodium fluoresem
are nuxed in solution leadmg to precipi-
tauon of benzalkonium fluorescemate Ttus
IS a sufficiently general reaction to warrant
the “rule of thumb” that large cationic and
large amonic molecules shoiud not be used
together
Changes of Solvent
Occasionally, it is necessary to change sol-
vents m a pharmaceutical preparation It has
been suggested that the solubility of a sub-
stance should be the same m two solvents
with the same dieleclnc constant^'' This
can of course be true only if the diclcctnc
constant is due prunanly to one type of mter-
action, e-g., polarizability This may be illus-
trated by the solubility of phenobarbital in
mixed solvents Consider the following
The approximate diclectnc constant
(A D C) IS calculated by neglecting volume
changes and usmg the dielectric constants
from Table 23 For example, the first value
is obtained as follows
A.DC s= 015 (21) +0 85 (80) =71 1
156 Solution Oosogo Forms
If one viiihcs to predict other solvent com-
binations It IS only necessary to know their
dicicctnc constant and to use ordinary alli-
gation methods
It IS dangerous to push this reasoning too
far For example, in Table 24 the solubility
mcrcoses as the A D C decreases Thus, it
might be expected that the solubility m
formamide would be quite small Actually,
the solubility is greater than that in ethanol!
This may be rationalized m terms of the bal
ance of high polarizability and dielectric
constant of formamide Phcnobarbital has a
high polanzability as well as permanent di-
poles, thus making formamide a very good
solvent
CFFCCT of pU os SOtUQtLlTY
The majority of organic medicinal agents
arc weak acids or bases ConsequenUy, the
solubility of these agents is stron^y depend-
ent on the pH of the solution A qualitative
understanding of this phenomenon is ob-
tained by assuming that the charged form
of the drug is more water soluble and the
uncharged form is tlicrcforc the solubility-
limiting species Thus, sodium phcnobarbital
IS freely soluble (1 Gm/ml) and phcoo-
barbital is only slightly soluble (1 Cm /800
ml), atropine sulfate is freely soluble (1
Gm/04 ml ) and atropine slighdy soluble
(I Gni/455 ml) The two ditTcrcnt ex
ampics were chosen to illustrate that the
charged species may be either the acid form
(atropine sulfate) or (he base form (sodium
phcnobarbital) of the medicinal This type
of reasoning is particularly useful m under-
standing the precipitation seen when a solu-
tion of sodium phcnobarbital is mued with
an acidic vehicle It is occasionally desirable
to put this qualitative reasoning on a quan-
titative basts This is easily accomplished
with the aid of the ' butler equation "*
pU = pK. + log|!!- (12)
where pH = — log hydrogen ion concen
trauon, pK 4 =r — log acidic dissociation
constant, Co = concentration of the basic
species and Ca = concentration of die acidic
Hecvlersoa tlusclbAch c<)uxtioa, c( page
5S
species The pH at which any drug will pre-
cipitate from solution may be predicted from
this equation by insertion of the proper
values The pK^ values and the solubiUttcs
are obtained from the literature f (If only
the pKs (2S°C ) values arc given, subtract
them from 14 to obtam the equivalent pK^
(25^0 ] One then inserts the molar con-
centration of the soluble form reduced by
the molar solubility for one concentration
term and the molar solubility for the other
This can probably be seen most readily with
an dlustmtion
At what pH would a soluUon of sodium
sulfadiazine (S^ ) precipitate from solution?
Sofubi/ity sulfodfazinc at 25‘’C = J Cmy
13 liter M W Sulfadiazme 250, sodium
sulfadiazine 272 pKa = 6 4S
pH = 6 48 + log
JO 0 077
272 250
0 077/250
s 643 + log-
=s 648 + 200 + 078 = 9 26
When tbe solubility of one of the species
IS low, the validity of the buder equation
should be checked The exact equation is
pH s pKa + log
Ctv + HaO+ - OH-
Ca-HjO+-J.OH“
(13)
As long as Ca and Co arc at least ten tunes
HjO+ or OH" concentration the simplified
version equation 12 is valid In the example
used here, Ca = 3 08 X 10-«M and OH"
Gf 0 18 X 10“* Thus the answer is correct
If the approximauons arc not good, one may
obtam a better value by inserting the ap-
proximate value and re solving Tlus may be
illustrated with the previous example
pH = 6 48 + log
0 184
308X IO-* + OOI8x 10-
= 9231
Note that the pH given m this answer is
sli^tly more acidic than the previous one
tUiclul sources Are references 7? SO la the
bibliography
t Qy & senes of sucb ItcriUoas the sniw-er may
bo r^itAincd lo any desired accuracy
Stability of Solutions 157
When the solubflity-limitmg species is the
acid species, any error of this nature will be
such that the predicted pH is too high If the
basic species is the solubihly-Limting species,
the inaccuracy will anse from HaO+ not
being much smaller than Cb The predicted
pH will therefore be too low The errors m
both cases are such that they give a margin
of safety to the predicted pH of precipitation
Therefore, the approximate equation (12)
serves the purpose of indicating a pH beyond
which precipitation is likely
Often, the vehicle containmg the drug will
be bydroalcohohc m nature The effect of
the alcohol will be twofold, it will change the
dissociation constant and it will mcrease the
solubihty of the less soluble (uncharged)
form The qualitative effect on the dissocia-
tion constant can be seen with the aid of
Coulomb’s Law (equation II) The intro-
duction of alcohol will lower the over-all
dielectnc constant and thereby mcrease the
work necessary to separate (dissociate) the
lotuc species This means that the equilib-
rium always be shifted toward the side
containmg the fewer charged speaes The
concurrent mcrease m the solubihty of the
uncharged species will be much larger Thus,
the over-all effect wiU be that the pH of pre-
cipitation will be shifted and the solubility at
any pH will be mcreased.
It must always be kept clearly m mmd that
mixing a weak acid with a weak base will
result m ncuttahzaivon Thus, if we mix solu-
Uoas of diphsnhydEanune hydrochloride and
sodium pentobarbital, we may get precipita-
tion of either or both or a salt of the two de-
pending on the relative amounts of each drug
used
Solubilization
One other means of effectmg soiutioa de-
serves attention This process is known as
“solubilization” and involves a colloidal solu-
tion the particles of which are capable of
mcreasing the ordmary solubility of a com-
pound This mcrease m solubility is due to
adsorption or mcorporation of the solute
molecules onto or m the colloidal particle
The colloidal particles usually consist of
many molecules of a suifaclanl arranged so
that the nonpolar portions of the surfactant
are mteimeshed The resultmg particle is
probably m the shape of a sausage, a sphere
or a sandwich and is called a micelle A
polarizable non-water soluble molecule may
then be mcoqwrated mto the micelle so that
its nonpolar portion is m juxtaposition to the
Boopolar portion of the micelle
Most of the properties of solubilized drugs
may be understood by assummg that the col-
loidal surfactant is simply a second mvisible
phase Thus, the effect of pH on the solu-
bilization of weak acids may be explained
by assuming that the surfactant is a second
phase m which the undissociated form is solu-
ble and the dissociated (charged) form is
insoluble **
The use of solubilizers in pharmacy dates
back to the 19th century However, their use
in internal preparations is relatively recent.
The sorbitan esters (Tweens® and Spans®)
have been widely tested and found to be
relatively nontoxic The use of solubilizers
has achieved success in vitamm formulations
to mcorporale the “fat’ soluble vitamms into
aqueous preparations Several studies have
shown that vitamm A is more stable and bet-
ter absorbed m a solubilized aqueous solu-
tion than in a true solution m an oil ^ The
absorption of iron is also mcreased by sur-
factants Other workers have found that
surfactants hasten the color fadmg of dyes,®*
and can decrease the effectiveness of pre-
servatives ® ** Therefore, it is necessary
that each preparation containmg a surfactant
be evaluated on an individual basis
STABILITY OF SOLUTIONS
Since DO medicmal m solution will be
stable forever, stability is only a relative term
In pharmaceutical practice, most products
have sufficient shelf hfe so that the patient
need take no special precautions However,
the student is aware that some products carry
expiration dates beyond which they should
not be used Other products require refnger-
ation and some must be protected from light
In order to understand need for the pre-
ceding precautions let us consider the fol-
lowmg experiment
An organic ester is dissolved m water and
the concentration of the drug is determmed
158 Sotuhon Dotogs Forms
Table 25
Time (days)
CoNCt.sTiwnoN (Gin./I00inl )
Slope
Slope/Concentratiom
0
600
»
_
4
3 90
-0 400
-0 103
8
255
-0 280
-0 110
12
165
-0 175
-0 106
16
105
-0110
-0105
20
0 70
— = - 106C
dt
at tunc micrvals o\cr a period of several da)s
The concentration may Uica be plotted as a
function of time as shoMii in Figure 6S The
slope of this curve at any point may be ob-
tained by determining the slope of the straight
fine (angenr to the curve at the desired point.*
For example, the slope at 4 days is computed
from the slope of the straight line shown m
Figure 6S drawn tangent at the 4-day potoL
The slope of the curve at other times is com-
puted in the same manner The slope may be
determined at several points and the follow-
ing data m Table 25 obtained
Note that the slope divided by the conccn-
C*-Ct
•This is done 4S follows m ss » < «■.— where
t»“t«
C« is the conccflUaiioQ at ume ti and Ci the cos
ccotrauoQ at time (k
tration is a constant This constant will be
designated k and Uic data m Table 25 may
now be presented m the form of the follow-
ing cquaiiOD
slope = iC - - D1D6C (J4)
*rhc slope has units of cooccniraiion per day
and may be expressed as
Where dC is the change in concentration m
the time period dt It is thus seen that the
slope IS the rate of disappearance of the drug
from the solution According to equation 14
this rate is proportional to the concentniUoo
of the drug in soluuon with proportionality
constant k
Stabilify of Solutions 159
Why IS the rate of degradation propor-
tional to the concentration m solution?
Assume that m the previous example the
drug IS disappearing due to the hydrolysis of
the ester linkage It then seems reasonable
that the rate of hydrolysis will depend on the
number of collisions per second between the
water and the drug molecules (Not every
collision will lead to hydrolysis, but a certam
fraction of the colhsions will do so ) In turn,
the number of collisions will depend on the
concentration of ester and water molecules
In dilute aqueous solutions the concentration
of water will be much greater than the con-
centration of the ester The number of col-
lisions per second ■will theieioie depend only
on the concentration of drug molecules in
the solution, smce a small change in drug
concentration will have virtually no effect on
water concentration Therefore, the rate of
hydrol>sis must depend only on the concen-
tration of drug m solution, as seen m equa-
tion 14
This type of rate equation is known as a
pseudo fint-order reaction The order of a
reaction is the sum of the exponents of all
concentration terms on the right hand side of
the equation The hydrolysis is actually sec-
ond order
4^=k'(C)(W) (15)
Where W = water concentration However,
the water concentration does not change dur-
mg the course of the reaction, being m great
excess, and may be mcorporated with the
rate constant k' to produce k and equation 1 4
If the amount of water is decreased (e g ,
by usmg propylene glycol m place of water)
to the point where the water concentration
IS comparable with that of the drug, the hy-
drolysis will depend on both drug and water
concentrations The slope of a plot of con-
centration of drug versus time would then
be divided by the product of drug and water
conantration to obtam the rate constant ^
Another type of behavior would be noted
if the satura^ drug solution were in con^/:t
with excess solid drug The concentration of
drug would now be constant, smce the solid
would dissolve as rapidly as the drug was
hydrolyzed However, we may detennme one
of the products of the reactions (e g , the al-
cohol) and plot its concentration versus time,
as shown m Figure 69 This plo. may be
represented by
This then would be a pseudo zero-order
reaction
Many other types of rate equations are
possible, dependmg on the mechanism of the
160
Solution Dosage Forms
rcactioa Nfany of the more complex cases
may be resolved into parallel or senes reac-
tions, each step of which is actually a zero-
order or a fint-ordcr reaction
Catalysis
A catal}^! may be dcHncd as a substance
which will greatly mcreasc the rate of the
reaction although it does not occur in the
stoichiometiy •
Probably the most common catalysts m
pharmaceutical solutions are hydronium and
hydroxide ions The hydrolysis of most drugs
will be dependent on the relative concentra-
tion of such ions In some reactions other
weaker acidic and basic species, c g ,
acetate ion, NHs may also be catalysts Most
kinetic studies of drug degradation will there-
fore include a “pH-rate profile** This is a
plot of the rate constant vs pH Such a plot
will make It possible to predict the pH of
maximum stability for a product For ex-
ample, the optimum stability range for aque-
ous solutions of potassium penicillin is found
to be pH 6 0 to 6 S
The effect of pH on hydrolysis may be
understood by mvestigation of the reaction
mechanism (step-by-step pathway) involved
In acid solution
are the ratc-limiimg (slowest) steps If it is
assumed that the ratio of the cquilibnum
constants for these steps is proportional to
the rate constants, then the relative rate in
acidic and basic media depends on the rela-
tive nucleophilic and electrophilic natures
O
of the reactants (OH^, HaO, R — and
+OH
R — C — ^X) 2* Usually it is found that the rate
constant for base catalysis is much larger
(200 to 1,000 tunes, or more) than the rate
constant for acid hydrolysis The total rate
of disappearance may be wntlcn
R = kj.(C) (H+) + k„(C) (OH-)
At pH 7 0 (H+ = OH~) the second term
will be about 1,000 times the first term At
pH 6 0 the second term will be 100 times
larger than the first term but the total rate
will be only one tenth the rate at pH 7 0 At
pH 5 0 the second term will still predominate
(10 tunes the first term) and the total rate
will be about one hundredth the rate at pH
7 0 "niercfore, it is apparent that most ny-
drolyzable mcdicmals will be much more
O OH OH OH
R-^-X + H+->R-^-X + HjOt.R-C-X-»R-C-X-{-H+
I I
OH
OHa
OH
and m alkalme solution
O
^R-C-l-X--*R-C-OH + HX
\h
o-
l
K-C-X + OH- -*R-C-X->R-C-l-X--»R-C-0_+HX
1 \
OH OH
^Vhcre X may be OR*, NH-, etc.
The reactions with an asterisk over them
* InvesUgation of the rate equatioa will show
that the rate is propomooat to the catalyst coo
ceotratioo. Since the catalyst cooccntratioo is coo-
-tant, the cooccntrauoa may be Incorporated into
u rate cooitanL
Stable at a pH of 5 to 6 than at more basic
pH values
Many other catalysts may be encountered
Inorganic heavy metal ions are often indicted,
and such unlikely things as sodium phosphate
may be catalysts under some conditions
It u imperative, then, that the degradation
Stability of Solutions 161
rate of a drug be determined in the final dos-
age fonn and not merely m an idealized aque-
ous solution
Hydrolytic Degradation
The most important cause of drug decom-
position IS hydrolysis This follows, smce the
majonty of organic medicinals are esters or
contam other groupmgs such as substituted
amides, lactones, lactams, etc , which are
subject to hydrolysis There are several ap-
proaches to this problem * The addition of
agents which form complexes with the drug
may decrease the hydrolysis rate sa z*
other method is often used with antibiotics
the drug IS packaged m a dry form from which
the pharmacist prepares a solution immedi-
ately prior to use Probably the simplest
method of stabilization is to decrease the
water concentration Thus, one may prepare
a relatively stable aspinn solution by replac-
ing water with alcohol and propylene glycol “
However, it should be noted that potassium
pemollin G is rapidly mactivated by the pres-
ence of alcohol' The problem with pemctl-
ha may be circumvented by preparation of
water-msoluble salts with large organic
cations replacing the potassium ion (cf the
section on solubility) Their low solubihty
strikingly reduces the degradation rate (equa-
tion 16) and makes a suspension which mam-
taiQs potency m a refrigerator for a year or
more Recent work has shown that dis
solving esters m a micellular solution results
m considerable stabilization of the ester ** **
Autoxidation Reactions
Another common stability problem is
autoxidation (oxidations involving atmos-
pheric oxygen) Many autoxidations mvolve
free radical mechamsms The basic scheme
for such reactions may be expressed as
follows
stand the various approaches to stabilization
The student will readily perceive that the
simple kmetic equations which work for other
reactions will not be useful here smce RH is
being destroyed by at least two different reac-
tions, A and C
The prevention of autoxidation may be
attempted by slowmg the mitiation reac-
tion A This can be accomplished by use of
dark or coated bottles if &e photoxidation
path IS important, and the use of chelatmg
agents such as ethylenediammetetraacetic
acid (Versene®) to remove trace ions which
are capable of reaction imtiation
Another widely used method is the addi-
tion of other easily oxidized substances (in-
hibitors) which are mcapable of chain prop-
agation
RO2 + IH I + ROjH
L prod
Thus, such substances as phenols and ammes
may be effective antioxidants, since cham
propagation requires the structure R 0 0 O
which IS quite improbable ‘ Often it is nec-
essary to stabilize phenolic and catechol types
of drugs (eg, epmepbrme) In this case it
IS necessary to use a stabilizer which under-
goes the miliauon step more readily than the
drug The ability of vanous antioxidants to
undergo the initiation step may be compared
using oxidation jTotentials
Useful antioxidants m oleaginous systems
are substances such as a-tocopherol, butyl
hydroxyanisole and ascorbyl palmitate In
aqueous systems use may be made of agents
such as sodium sulfite, sodium formaldehyde
sulfoxylate, sodium bisulfite and ascorbic
acid It is often found that the mixture of
two or more antioxidants is synergistic, lead-
ing to a much larger mcrcase m stability than
predictable from simple additivity
A
— rr-
heavy melals
R.
iniUatioa
B
R + Og ->
ROg
cham propagation
C
ROg + RH -*
R +RO2H
cham propagaUoo
D
ROg + RO2 -»
products
cham termination
concurrent reactions may
be Hydrogen ion conccntrati
written but these few will enable us to undcr-
* The contiol of pH has already been discussed
an effect on oxidation rate In the case of
phenohe oxidation the removal of an electron
t62
Solution Dosage Forms
seems to be easier than the extraction of a
h)drogcn atom
1 11 HI
Maintenance of a low pH will prevent ioniza-
tion, decrease the concentration of species
II, and thereby produce significant stabiliza-
tion of the molecule
The autoxidation of oils m surfactant solu-
tions IS quite mtcrcsting Starting with an
emulsion of the oil and adding surfactant m
steps until a clear solubilized solution is ob-
tained, the oxidation rate at first mcreoscs
and then decreases greatly when solution is
complete This behavior has been explained
by assuming that the miuatioa step is tokuig
place m the micelle and propagation in the
oil phase Thus, complete solution is equiva-
lent to addition of a cham inhibitor *
ElTcct of Temperature, hfost drug degrada
tions increase rapidly with mcrcasmg tern
perature The quantitative expression of this
met IS known as the Arrhenius equation
® ki T303T\ Ti X Tj /
where ki is the rate comtant at temperature
Ti, ka IS the rate constant at temperature T:,
and Ea IS known as the ‘activation energy'*
of the reaction The mcrcosc m rate constant
IS undesirable m itself The most ocsirable
method for avoidmg contommation is the
use of aseptic techmc and sterilization of the
solution This is of utmost importance m the
preparation of parenteral and ophthalmic
preparations However, m most oramory m-
ten^ and external preparations, the rather
tedious and expensive manipulations of asep-
tic techmc are not necessary The problem
of contommation may be minimized by the
use of suitable antimicrobial or antifungal
agents
The common phamuccutical solvents al-
cohol and glycerol ore known to possess
antimicrobiiU properties In addition, the
presence of sucrose m high concentration is
a useful preservative Thus, alcohol m con-
centration of 15 per cent or higher, glycerol
at 50 per cent or higher and sucrose solutions
of 65 per cent need no other preservatives
When used in combmation, the amounts may
be less for each ingredient^
It IS often desirable to add an antibacterial
agent to the solution Several agents arc avail-
able for this purpose, the most widely used
agents being benzoic acid and the esters of
p-b>drox)bcQZOic acid.
Benzoic acid is a far more effective agent
than sodium benzoate, therefore, the pre-
servative action must be strongly dependent
on pH The usual effective conccnuation of
benzoic acid is 0 1 per cent The concentra-
witb temperature is rationalized in terms of
the increased fraction of molecules having
sufficient energy for reaction Many of the
common reactions have activation energies"
of about 12 kilocalories per degree per mole
Solving equation 17 at this value leads to the
approximate rule that reaction rate doubles
for each 10-dcgrcc nsc m temperature
This readily explains the rationale for
keepmg medications m the refrigerator The
degradation rate will be decreased to ap-
proximately M of Its degradauon rate at
tion of benzoic acid necessary to mamtain a
tree acid concentration of 0 1 per cent in a
solution with a pH of 6 0 would be about
6 5 per cent (pK^ of benzoic acid is 4 20 )
Because of this, other agents are needed
for Donacidic solutions This need has been
fiUed by the use of the methyl, ethyl, propyl
and butyl esters of p-hydrox) benzoic acid
(parabcos) The high pK^ of the phenolic
hydroxy group (ca 10) makes their use
feasible m almost all pharmaceutical prep-
arations
room temperature
These esters differ in their relative activity
Decradatiom by Micro-organisms
Although a completely different phenome-
non, the growth of micro-organisms m solu-
tions may lead to loss of potency In many
eases (c g , ophthalmic pieporations) the
presence of viable organisms in the solutions
* Note the unulanty to eqiutioa 10
against vanous types of micro-organisms
Therefore, use is made of mixtures of para-
bens as preservatives The concentration
needed u difficult to ascertain, since the rec-
ommeoded concentrations are often higher
than the water solubility of the porat^ns
Solubiu^ data arc given m Table 26
In practice a problem arises in the use of
Coloring and Flavoring 163
Table 26
Paraben
Water
Propylene
GLYCOL
Alcohol
Solubility m Gm /lOO ml
Methyl
025
22
52
Ethyl
017
25
70
Propyl
0 02
26
95
Butyl
0 02
110
210
parabens because of their very slow rate of
dissolution This may be averted by the use
of stock solutions m propylene glycol
Another problem is Ukely to arise when
parabens are used m solutions containing
other molecules with which they may mter-
act through formation of hydrogen bonds
The mteraction with Tween 80® has been
thoroughly studied “ The reaction may
be written
Tween Paraben = Paraben-Tween
Hus reaction will follow the law of mass
action and may therefore be wntten
(Smce only the free paraben is aobbac-
tenal, it is necessary to add extra paraben to
a solution contaming such agents ) The total
araben needed is the desired free paraben,
, plus the amoum in the complex form, P-T
Paraben needed = [PJ + [P T] = [PJ + KFUIPJ
= Pn+K(T)3
When P and T are expressed in percentage
the value of K for propylparaben is about
0 65 and for methylparaben 4 5 The use of
this equation has been shown to predict the
required paraben concentration quite accu-
rately®® The use of preservatives m oph-
thalmc solutions will be discussed m a later
section
COLORING AND FLAVORING
Coloring
Occasionally the pharmacist encounters a
prescnption m which coloring will mercase
patient acceptance A targe number of coa l
t ar colors are available for such use Prob-
ably the easiest ap^ach to tbe^ problem is
the use of hquid food colors available in
grocery stores Such Food, Drug and Cos-
metic dyes are not, m general, as stable as
Drug and Cosmetic dy es However, for use
m extemporaneous compounding where long-
term stability IS not necessary they are quite
useful They consist of solutions of 3 to 4
per cent colormg agent m a propylene glycol-
water vehicle The usual colors are blue.
green, yellow and re^ Other colors are easily
obtained' byT appropnate mixtures of these
The dyes are all sodium salts sulfomc
aad s Thus, one would anticipate possible
mcompatibilities with large catiomc molecules
such as the salts of alkaloids However, be-
cause of the very low concentration of dye
m the final product (ca 5 X no
problem is usually observed Smce sulfomc
acids are quite strong, the dyes are not pre-
apitated by ordinary acidic vehicles, al-
though the color may be shghtly altered. It
IS interesting to note Aat recently some water
soluble F D C dyes have been reacted with
large cationic surfactants to obtom oil soluble
dyes
Flavoring
In the past several years patients have
come to expect pleasanuy flavored medica-
uot^ Pharmaceutical manufacturers assure
flavor acceptance by testing formulations with
flavor panels Of course, such procedures are
not available to the pharmacist and he must
depend on the few general flavoring pnn-
aplcs which he may obtain ® **
Flavor is a very subjective sensation de-
pending on taste, feel, color and odor Such
a complex phenomenon cannot be described
by mathematical formulae Research in the
past few years has led to the realization that
taste and odor are both adsorption pbe-
oomena ** Further studies will probably
lead to understanding of taste and odor dif-
ferences on the basis of chemical structure
Even this knowledge would not make flavor-
mg a science, since difference m taste and
odor response due to age, genetic differences
and other factors would still exist
la attempting to produce pleasantly fla-
vored liquids extemporaneously the pharma-
cist must keep several general ideas in mind
The objectionable taste is ideally blended
into a taste complex the over all effect of
164 Solution Dosage Forms
which 1 $ pleasant Caic must be taken to
avoid an unpleasant aftertaste which may
destroy the over all effect (Occasionally, it
IS well to advise the patient to nnsc his mouth
after taking his medication ) Another im>
portant consideration is the difference be-
tween flavor masking and flavor acceptance
Although gI)C}rThiza S)rup is an excellent
masking agent for many mcdicinals, few pa-
tients approve of its taste-’ -* It should be
noted that the masking properties of gly-
cyrrhiza may be due m part to precipitation
of insoluble salts Cationic drugs may inter-
act with the large gl)C)nhi2a anion and thus
reduce the therapeutic efficacy of the drug
The factors to be considered and the steps
to be taken in flavonng a liquid medicinal
may be outlined as follows
1 Age of Patient
A Pediatrics
Sweet candy and fruity flavors
B Adults
Citrus less sweet
C Genatnes
Mint wine, liquors
2 Taste to be masked
A. Salty
Syrups Raspberry, curus. orange
flavors cocoa cherry, cinnamon
Elixirs Gl)cyrrhiza aromatic
Eavon Maple butterscotch, grape,
honey, licorice raspberry
B Bitter
S)Tups Cocoa glyc>rrhiza aromatic
enodict>on citric acid
Elixirs Aromatic
Flavors Chocolate mints, raspberry,
honey wild cherry
C Sour or Acid
S)rups Raspberry, citrus orange flavor
Elixirs Aromatic
Eavors Citrus raspberry
3 Color
Match flavor if possible
4 Texture
A. Mouth feel may often be unproved by
addition of an agent which increases
viscosity such as sorbitol (also imparts
sweetness) or gums
B Oily taste may be improved by the
use of mint, vanilla or ciUus flavors.
Often, large pharmacologic groups of
agents have common taste problems which
may be attacked m a similar manner
Antibiotics. Bitter taste requires sweeten-
mg agent such as_juc_rpsc,__sacchanne or
cyclam ates (sodium or ca lcium) m addition
to the follow mg
Banana Lemon
Cherry Mint
Orange Raspberry
Pineapple Chocolate
Antihistamines have a salty taste as well
as a stinging ' sensation on the tongue
Citrus Root Beer
Raspberry Honey
Wild Cherry Peach
Apneot Custard
Non-narcotic Analgesics.
Citrus Root Beer
Banana Wmtergrecn
Narcotic Analgesics
Butterscotch Apneot
Cherry Liconce
Raspberry Vermouth
Barbiturates Usually somewhat bitter and
require sweetening
Citrus Raspberry
Mint Anise
Vitamm Preparations,
Raspberry VaoiUa
Cherry Cheny
Chocolate mint Citrus
Several sweetening agents are available for
use as flavor adjuncts Sucrose and sorbitol
may be used in high concentrations as both
sweetening agents and to improve “mouth
feel ' More intense sweetening is obtamed by
the use of cyclamatc or sacchann, the latter
bemg less desirable because of its tendency
to hydrolytic breakdown over long penoe^
of tune It IS obvious that no pharmacy would
wish to stock the large number of different
flavonng agents noted above Careful pe-
rusal of the lists wiU show that several flavor-
mg agents appear several times It may well
be practical for the pharmacy to carry a few
flavonng agents which will produce reason-
able pr^ucls m each ease It has been sug
^sted that cherry, chocolate, mint, orange
and raspberry would be sufficient to solve
most flavoring problems ”
All such agents should be kept in small
dark ^ass containers in a cool place to pre-
vent dwomposition of the flavor
The student will recall from his cxpcncncc
m prepanng aromatic waters that many
Special Solutions 165
flavonng agents are not very water soluble
However, adequate flavoring can be obtained
using only mmimal amounts of flavoranls
The use of suitable diluting technics with
flavorants may therefore be necessary
PACKAGING
The student is familiar from his labora-
tory studies with the ordinary glass bottles
used for packaging hquids The need for
brown bottles which absorb the highly ener-
getic blue wavelengths should be apparent
from the earher discussion of autoxidation
The green dropper bottles often used will
transmit ultraviolet radiation and are there-
fore no improvement over clear bottles
The past few years have seen the intro-
duction of plastic contamers for liquids They
have certam advantages m terms of break-
age and opacity However, their ability to
adsorb preservatives and drugs and allow
free passage of gases militates against their
usage m several systems Their use for
any product must be tested on an mdividual
basis, and it will probably be several years
before they may be used widely in prescnp*
tioa practice
SPECIAL SOLUTIONS
Although the general principles developed
earlier are applicable to all solutions, some
dosage forms require special technics
Ophthalmic Solutions
It IS generally agreed that ophthalmic solu-
tions should be sterile, should contam a pre-
servative and should have an osmotic pres-
sure and pH similar to that of normal lacn-
mal fluid Each of these requirements will be
discussed separately
Sterdity. It seems sclf-cvidcnl that any
ophthalmic solution should be sterile Since
1953 ophthalmic solutions which are not
sterile have been considered adulterated and
misbranded by the FDA In the legal sense,
this rulmg applies only to commercial prep-
arations, but the moral obligation of the retail
pharmacist is clear Although many different
organisms may cause damage m the e)c, the
most senous imection is due to Pseudomonas
aeruginosa (Bacillus pyocyaneus) These
gram negative bacilli were a common cause
of wound infection before the days of aseptic
surgery The orgamsm may be found in the
mtetinal tract or the normal skm of man
and may be an airborne contammant Thus,
contamination of ophthalmic solutions is not
surprismg if the solutions are not properly
handled The seriousness of Pseudomonas m-
fections may be brought home by an ex-
amination of the clinical literature which
abounds with terms such as enucleation of
the eye and corneal transplants ^ No phar-
macist would want the responsibihty for
blindmg a patient
In onier to ensure stenhty of the final
product, the solution should be prepared
under aseptic conditions The ready availa-
bihty of pressure cookers makes it possible
to sterilize both the apparatus used m fillmg
and the flna} prescription It is also possible
to render solutions stenle by filtration tech-
nics These have been made practical by the
advent of the Millipore® filler * This filter
(MF HA) with the use of a Swinny adapter
on a syrmge makes it possible to remove all
bacteria from a solution This method is par-
ticularly useful for filling a large number of
units of the same solution Its usefulness
as a general method for individual prescrip-
tions is decreased by the necessity of auto-
claving the filter assembly before each use
With such technics it is possible for the orig-
inal prescription to leave the pharmacy m a
stenle condition However, the pharmacist’s
respcmsibihly does not end here
Prescrvalnes. Attention to the future use
of the final product is also unportanL If the
solution IS to be used m a physician’s office
or a clinic, the possibility of moculation of
pathogens mto the solution becomes great
For example, an epidemic of Pseudomonas
infection in a Rotterdam hospital, a few
years ago, revealed that a large number of
eyedrops m clinical use were mfected Fur-
ther study of the solutions m use m the con-
sulting rooms of 12 eje surgeons m Rotter-
dam showed contammation m at least one
preparation in each of 9 of the 12 rooms
examined ** Thus, it is necessary that oph-
thalmic solutions for such use be “sclf-
stcnhzmg ” Solutions for home use are much
*lQformatioa is available from tbe Millipore
Co, Bedford, Mass
166 Solution Dotage Forms
less liable to such “cross lafcctioas," but it
seems reasonable to use a preservative for
this t)pc of preparation also A third general
t)pe of c)c medication is more likely to be
seen only in hospital pharmacies Prepara-*
tions for use m traumatized e}cs or during
surgery should be compounded for the use
of only one patient Smcc all preservatives
arc somewhat imtating, and smee this prep*
aration will only be used once, preservatives
should be omitted-®® ®*
The problem arises as to what preservative
should be used This is a particularly knotty
problem which has puzzled investigators for
several )cars The literature is conflicting
and confusing and the populanty of various
agents rises and falls with alarming rapidity
It seems unlikely that much can be gamed
by reiteration of the history of such preserva-
U\cs Therefore, only a few examples which
ar^resently accepted will be discussed
Ine quaternary ammonium compounds,
especially bcnzalkonium chloride, have be-
come accepted as excellent broad spectrum
preservatives eflcciivc against both gram*
positive and gram*oegaUve organisms*®
However, there has been a question raised as
to their cfTcctiveacss against certain strains
of Pseudomonas ®® It has been suggested that
the addition of 001 to 0 1 per cent of
disodium cthylcncdiammctetraacctatc will
make such resistant organisms susceptible to
the usual I 10 000 IXQzalkoaium chlonde
solutions*® ®® A recent publication suggests
that a mixture of bcnzalkonium chlonde
(0 02%) and neomjem sulfate (0 5%)
might be an excellent combination ' * An
other possibility is bcnzalkonium chlonde
(001%) and polymum B 1,000 um(s/cc
The use of poI>mixm B has been questioned,
since It 15 one of the few drugs useful against
clmicol mfcctions of Pseudomonas Recent
development of a new antibiotic useful against
Pseudomonas mfcctions seems to reduce the
validity of this argument ®* Note that the
need for bcnzalkomum chlonde is due to the
narrow spectrum of either of the suggested
antibiotics
The quaternary ammonium preservatives
have some incompatibilities which must be
taken mto account with their use They have
been reported to be incompatible with 5 per
cent (but not 2% ) bone acid, miratcs, salt-
i^lates and fluorcsccm Fluoreseem solutions
are a notonous source of Pseudomonas in-
fections and the UJJ* suggests that only
single dose preparations should be used
In the case of mtrates and sahcylates where
the cation is the pharmacologically active
agent, the best method is to change to the
cUonde or another salt which would be com-
pauble with quaternanes One other effect
of the addition of bcnzalkonium chlonde
should be noted The surface tension reduc-
tion will decrease the drop size of the solu-
tion with concurrent reduction in dosage per
drop (The drop is reduced from 0 05
cc/drop to about 003/drop m a 001%
solution )
Chlorobutanol has been strongly recom-
mended in the past ®® However, it has some
distmct disadvantages It is difficult to effect
solution of the OS per cent concentration
required and it is rapidly destroyed by auto-
claving or in basic solution It u also incom-
patible with stiver nitrate and sodium salts
of sulfa drugs **
The organic mercunals such os phenyl-
mercunc nitrate have been used for several
years as preservative agents ** Unfortu-
nately, organic mercurial agents arc much
slower acting than other agents and tend to
be sensitizing when used over long periods of
tune Phenylmercuric nitrate is also mcom
patible with bolides, which further detracts
from Its usefulness It may be used with
salicylate and nitrate salts m place of
quaternanes Thunerosal has recently been
recommended for ophthalmic use m com-
bination with polymizin B It worked well
at the pH tested by the authors (6 8) but
could not be used at more acidic pH values
because of precipitation of the free acid form
ofiiumerosal
No other preservatives seem to have had
sufliaent testing to warrant their use m pref-
erence to those discussed
Osmotic Pressure. A few years ago a great
deal of energy was expended in the effort to
assure the correct osmouc pressure of oph-
thalmic solutions Today, it is possible to
read m an Italian pharmaceutical journal a
quotation from a Swiss pharmaceutical
journal, which onginatcd in an Amcncan
pharmaceutical journal, that assures us that
osmouc pressure is rclauvciy unimportantl**
Special Solulions 167
This viewpoint is based on the fact that the
eye is insensitive to a rather large range of
osmotic pressure Hus concept has been
challenged on the grounds that although
pain may not be elicited, tearmg may result,
and, thus, medications may be washed out
of the eye Therefore, it seems that the
safest method is to adjust the osmotic pres-
sure of solutions for use m the eye to a
practical range
The student will recall the earher discus-
sion of Raoult’s Law This law states that
the vapor pressure above a liquid is propor-
tional to the mole fracUon of the liquid m the
solution Thus, as the mole fraction of solute
is mcreased the mole fraction of solvent will
decrease (sum of all mole fractions must
equal one) and the vapor pressure of the
solvent must necessarily decrease Let us now
visualize an aqueous soluuon and pure water
separated by a membrane which will allow
water molecules to pass freely but will not
allow the passage of solute molecules (Fig
70) Smce the vapor pressure of the water
IS greater than the vapor pressure of the solu-
tion, water will pass through the membrane
mto the solution In order to prevent this
transfer we may increase the pressure on
compartment B (Fa) with the piston until
the volume of water m B no longer mcreases
with time Thus, we have mcreased the vapor
pressure of the solution until it is equal to the
vapor pressure of the pure water Osmotic
pressure r is defined as the difference in pres-
sure necessaiy to prevent passage of solvent
in one direction, i e ,
’r = Fa-F^
It may appear that the osmotic pressure
should be a rather small force, since the
vapor pressure differences are quite small for
dilute aqueous solutions vs water This is
far from true, osmoUc pressures often being
as high as several atmospheres of pressure!
The explanation for this lies m the fact that
large increases in applied pressure must be
exerted m order to produce small mcreases
m vapor pressure The equation relatmg the
tu'o pressures is
2 3RT
V
log-
L
"a
A
WATER
1
1
1
1
1
1
B
SOLUTION
Fig 70 Water (A) and an aqueous
soluuon (B) separated by a semiperme
able membrane with impervious pistons
exerting pressures and Fb, respec-
tively, above each compartment
where R and T have their usual meanmgs,
V IS the volume per mole of liquid (eg, 18
ml /mole for water), P* is the vapor pres-
sure when F (apphed pressure) is zero and
p IS the vapor pressure for a given value of
F From this defimuon we may derive a re-
lationship for predictmg ir for various con-
centrauons of solute
„ 23RT, Pb 23RT, P*.
“ Fa — log— oc-sr-
V ®P B V i
Now, Pa = Pb (vapor pressure of water and
soluuon are equal), Pa* = Pw* where Pw® is
the vapor pressure of pure water, and Pa* =
Pn-® Xw = Pir® [I — X,] where is the
mole fracUon of water and X, is the mole
fraction of solute m the solution
Thus,
23RT, PbP*a 2 3RT ,
Pw*[l-XJ"
2JRT
V
Iog[l-X.I
For dilute soluuons, [1 — X,1 approaches
one and 2 3 log [1 — X,] is approximately
equal to — X» (The student may verify this
by checkmg the equality for smdl values of
Therefore
168 Soluhon Dotog« Formt
By dcfiniLioa,
__ moles solute (m)
moles water + molcjsoluie '
and for dilute solutions, where the moles of
solute arc much smaller than the moles of
water,
^ _ moles solute (m)
* ~ moles water
The moles of water multiplied by the volume
per mole gis cs the volume of w ater (V)
Thus,
r = -iRT=00S2MT (18)
where M IS the molarity of the solute We
may predict the osmotic pressure of a 5 per
cent glucose solution (which has the same
osmotic pressure as lacnmal Ouid) at 25*’C
as follows
» = 0 082 X ^ X 298
s 6 8 atmospheres ~ 100 Ib /in ^
The vapor pressure diflcrcntiai (Pw* •— p)
producing uus osmotic pressure may be csu>
mated with the aid of Raoult’s Law to be
only 2 78 X 10“* mm of mercury or 5 6 X
10“*lb/ta^
The effect of 100 Ib/m^ on a semi'
permeable membrane such as the cornea of
the C)e IS easily understood Such pressures
would neser actually be obtamed with oph'
tholmic medication, smee the pressure differ*
cntial would have to be generated by move*
ment of water molecules across the cornea
The stimulus will of counc induce lacnmal
secretion which rapidly dilutes and washes
out the offending liijuid.
Incorrect answers arc obtained if one at-
tempts to use equation 18 for predicting the
osmotic pressure of electrolytes This may be
explained by assuming that the molecules dis-
sociate mio g particles The mole fraction of
solute X, will then be multiplied by g
V _ (g)(m)
moles water
For exninple, with potassium chJonde, the
number of moles toth of potassium and
of cblondc ions are equal to the number of
moles of potassium chlonde added and the
total number of moles of solute is therefore
doubled by dissociation Of course, dissocia-
tion IS never complete and the factor g is
always less than the theoretic number of
particles possible It is therefore necessary
to determine the factor expenmcntally The
expenmenta] correction factor is usually
designated as i Equauon IS then becomes
vss0082iMT* (19)
Fortunately, u is not necessary to obtain
1 values for aU salts encountered, since the
variation between salts of similar t^pcs (e g ,
NaCI and KG, or MgSOi and CaSO^) is
nc^gible They also vary somewhat with
concentration hut this effect is also unim-
portant for practical compounding A list-
mg of 1 values is given m Table 27
*KooMU]g i anj 7 (6 8 atmospheres) it tbere
lore » pouitile to detemune the molanty of any
subsunce ncccsuxy 10 prepare an iso-osmoiic solu
uoo.
Table 27 Average i Values for Various Ionic TvPEst
TVpb
iVasuB
Hxampixs
Nonelcctrolylcs
10
Sucrose, dextrose, Rlyccrm
Weak cleclroljtcs
1 1
Pbcnobarbilal, bone acid
Urn univalent clcctroI)'lei
1 8
Sodium chlonde, procaine HQ, sodium
phenobarbital
Um-divalent e]cctrol> 1 es
23
Atropine sulfate, calcium sulfate
Di*uaiva]ent electrolytes
Z6
Calcium chlonde
Di-divalent c]ccirol)tct
1 1
Zinc sulfate, calcium sulfate
Uni tnvalcnt electrolytes
2.8
Sodium Citrate
Tri-univalcnl electrolytes
32
Feme chlonde
Tetraborate electrolytes
41
Sodium borate
t Modi&eJ from Wetli, J 2if Am Phann. Am. [PrxL] J 99, 1944.
Speciol Solutions 169
Two solutions which have the same dilonde sufBcient to make the final pcrcent-
osmoUc pressure are defined as iso-osmotic age 0 9 The sodium chloride equivalent E is
The term isotonic is more widely used m found m the following fashion
pharmacy This term is defined m terms of Now, E is the number of weight units of
an actual cell membrane For example, a sodium chloride equivalent to one weight unit
solution m which a red blood cell neither of the other solute, therefore the two ir may
swells nor shrinks will be isotonic with the he set equal and solved for E
red blood cell contents The term is often 24 5 i i
loosely used and the possibility that one of ^ = 32 x (20)
the solutes penetrates the membrane should
not be overlooked When penetration occurs. Knowing the value of i and the molecular
the solution may be iso osmotic but not iso weight of any given drug makes it possible
tome ** Lacrimal fluid (and blood plasma) to obtain the required value of E E will have
has been found to be isotonic with 0 9 per any weight umts as desired Thus, it is the
cent sodium chlonde “ Most practical number of grams equal to 1 gram of the m
methods of preparmg isotomc solutions use gredient, or, equally well, the number of Gm
this concentration as a guide “ Thus, m equal to 1 Gm of the ingredient A listing of
the sodium chlonde equivalent method the useful E values is given m Table 28 (Note
concentration of each mgredient is changed that many of these values are expcmncntal
(mentally) mto the equivalent amount of and may differ slightly from values calculated
sodium chlonde and adds additional sodium with the aid of equation 20 )
wt l^acl
(Osmotic pressure of NaQ) s: r^ s 0 082 X I 82 X — — X 298 k 0 76 X wt NaCl
Osmotic pressure of one weight umt of solute
= t, = 0 082xiX jj^x29S = 245i/MW
Table 28 PartI
Sodium Chloride Equivalents op Dru gs Usually Availa ble in Pure Form
AcnflavineNF 0 10 Ben^l alcohol N F 0 17
Alcohol U S P 0 65 Bismuth potassium tartrate N F 0 09
Alcohol, dehydrated N F 070
Alum (potassium) N F 0 18
Ammophyllme U S P 0 17
Amiodo:^! benzoate 0 20
Ammonium chlonde P 1 12
Amobarbital sodium U S P 0 25
Ampbetanune phosphate N F 0 34
Amphetamme sulfate U S P 0 22
Amprotropine phosphate 018
AmylcaineHCl 022
Antimony potassium tartrate U S P 018
AntipyrmeNF 017
Apomorphine HQ U S P 0 14
Arecoline HBr N P 0 27
Arsenic Inoxjde N F 0^0
Ascorbic acid P 018
Atropine sulfate P 013
Aurolhioglucose N F 0 03
Bacitracin P 0 05
Barbilal sodium NJ? 030
Bismuth sodium tartrate 0 13
Bone acid U S P 0 50
Butacame sulfate N F 0 20
Butethaixune formate 0 26
Caffeine U S P 0 08
Caffeine and sodium benzoate U S P 0 26
Caffeine and sodium salicylate N F 0 21
Calcium aminosalicylate U S P 0 27
Calcium chlonde U S P 051
Calcium chlonde ( 6 H 2 O) 0 35
Caldum chlonde, anhydrous 0 68
Calcium gluconate U-S P 0 16
Calcium lactate N F 0 23
Calcium levulmate N F 0 27
Calcium pantothenate U5 P 018
Chuuofon U S P 013
Chloramine TNF 023
CHorobutanol (hydrated) P 0 24
Chlortetracycline sulfate 013
OtnC acid U5 P 018
170
Solution Dosage Forms
Table 28 Part 1 (Continued)
Sodium Chloride Equivalents op Drugs Usually Available in Pure Form
Cocaine HCl U5 P
Codeine HQ
Codeine phosphate U S P
Cupnc sulfate N F
Cupnc sulfate, anh}drous
Dextroamphetamine phosphate
Dextrose P
Dextrose, anhydrous
DibucaiacHClUSP
Dihydrostreptomycia sulfate U S P
Emetine HD U S P
Ephcdrinc HCl N F
Ephednne sulfate U S P
Epiocphnne bitartrate U S P
Ergonovine roaleate U S P
Ethasenne HQ
Eth)Iencdiamine
Etb)lh}drocuprcine HQ
Ethylmorphine KC! U S P
Feme ammomum citrate, Green N F
Ferrous gluconate P
Ferrous lactate
Fluorescein sodium U S P
D Fructose
Galactose
D-Glueurooie acid
LGlutamic acid
Glycerin P
Cuanidme HQ
Hepann sodium Uil P
Hippuran®
Holocaine® HQ
Homatropine HOr U S P
HomatzopiDe mclhylbromide VSP
Hydrasljoc HQ
Hydroxyquinoline sulfate
Hyoscyamine HBr N F
H) oscyamine sulfate N F
Intracaine HQ
Isomazid P
016 Mercury bichlonde U S P
OIS Methacholine chloride U S P
014 Methadone HQ U^P
018 Metfaamphctamioe HCl U S P
0 27 Methcnamine U S P
» Methionine N F
MHhylatropioe bromide
^ . Monoethanolamme N P
Q I® MorphmeHClU^P
Morphine nitrate
“ Morphine sulfate USP
010
0 3Q Harcotme HQ
0 23 Keomyem sulfate USP
Q ig Nicotinamide USP
Q |g Nicoiuuc acid USP
0 12
^ ^ “Paolhesine
Q j_ Papavenne HQ USP
^ , , Penicillin, potassium CUSP
Penicillin, sodium G U S P
0 17 Pentobarbital sodium USP
0 IS Pentylenetetrazole U^ P
0 21 Phenindamine tartrate USP
0 31 Phenobarbital sodium USP
018 Phenol USP
- Phenylpropanolamine HQ
Q i® Physosugmme salicylate U^ P
^ Physostigmine sulfate
Pilocarpine HQ U S P
Pilocarpine nitrate USP
^ Polymyxin B sulfate USP
0 08 Potassium chlorate N F
0 10 Potassium chlonde USP
0 20 Potassium Iodide USP
0 17 Potassium nitrate N F
019 Potassiumpcnnangai}aleU.SP
0 IS Potassium phosphate N F
P2I Potassium phosphate monobasic
019 Potassium sulfate
0 14 Procainamide HCl USP
Procaine HQ U^ P
023 Propylene glycol U^ P
025 PyndoxineHQU^P
013
0 32
0 18
037
0 23
028
014
053
015
019
014
010
on
026
025
0 18
010
0 18
018
025
022
017
024
0J5
038
016
013
024
023
009
049
0 76
0J4
0 56
039
046
044
0 44
0 22
021
045
037
Lactic acid U^ P
041
Lactose U^ P
007
Magnesium chlonde
045
Magnesium sulfate P
017
hfanmtol N F
017
Menadione sodium bisuliile U.S P
020
Mependme HQ P
022
Mephencsin N P
019
Mcrbroimn N F
014
Mercunc cyanide
015
Qmnidine sulfate U S P 010
Quinine bisulfate N F 0 09
(^inme dihydrochloride N F 0 23
Quinine hydrochloride USP 014
Quinine and urea hydrochloride NJ’ 0 23
RaccphcdrineHQNP OJl
Resorcinol U^ P 0 28
Scopolamine HBr U^ P 012
Scopolamine methylmtrate 016
special Solutions 171
Table 28 Part 1 {Continued)
Sodium Chloride Equivalents of Drugs Usually Available in Pure Form
Secobarbital sodium U S P 0 24
Silver nitrate U S P 0 33
Mild Sliver protem N F 0 17
Strong sflver protem N F 0 08
Sodium acetate, anhydrous 0 77
Sodium acetate N F 0 46
Sodium aminosalicylate U S P 0 29
Sodium antimooyl tartrate 0 13
Sodium arsenate, dibasic 0 25
Sodium ascorbate 0 33
Sodium benzoate U S P 0 40
Sodium bicarbonate U S P 0 65
Sodium biphospbate, anhydrous 0 46
Sodium biphosphate U S P 0 40
Sodium bipbosphate { 2 H 2 O) 036
Sodium bisulfite U S P 0 61
Sodium borate U S P 0 42
Sodium bromide U S P 0 57
Sodium cacodylate NF 032
Sodium carbonate, anbyd 0 70
Sodium carbonate, monobydrated U S P 0 60
Sodium chloride U S P I 00
Sodium citrate UJ5 P 031
Sodium hypophosphite N F 0 61
Sodium iodide U S P 039
Sodium lactate 0 55
Sodium metabisulfite 0 67
Sodium nitrate 0 6S
Sodium nitrite U S P 0 84
Sodium phosphate exsiccated, N F 0 53
Sodium phosphate N F 0 29
Sodium phosphate, dibasic (2HiO) 0 42
Sodium phosphate, dibasic (l2HaO) 0 22
Sodium propionate N F 0 61
Sodium riboflavin phaspbsie 00^
Sodium salicylate U S P 0J6
Sodium s^f ate NP 026
Sodium sulfate, anhydrous 0^8
Exsiccated sodium sulfite N F 0 65
Sodium thiosulfate N F 031
Sorbitol H 2 O) 0 16
Stibaimne glucoside 014
Streptomycin sulfate U S P 0 07
Strychnine HCl 018
Strychnine nitrate N P 012
Sucrose U S P 0 08
Sulfacetamide Sodium U S P 0 23
Sulfadiazine Sodium U S P 0 24
Sulfamerazine Sodium U S P 0 23
Sul/apyndjoe sodium 0 23
Sulfatbiazole sodium N P 0 22
Tannic acid N F 0 03
Tartanc acid N F 0 25
Tetracaine HCl U S P 0 18
Tetraethylammonium bromide 033
Tetraetbylammooium chlonde 0 34
Theophylline U S P 010
Thiamme HCl U3 P 0 25
TubocuRinne chlonde U S P 013
Urea U3 P 0 59
UretbanU3P 031
ViomyciQ sulfate 0 08
Zmc chlonde N F 0 61
Zinc pbenolsulfonate N F 018
Zinc sulfanilate 0 21
ZmcsulfateUSP 015
Zmcsul/alfi dried 023
Table 28 Part 2
Sodium Chloridb Equivalents op
Adrenalone HCl
9 Aminoacndine HCl
Amydncame HQ
Amydnauoe mtrate
Antazoline HQ U S P
Antazohoe phosphate
Aranthol®
Atropme methyl xutrate
Benoxinate HQ
Benzalkonium chlonde U3 P.
Benzetbomum chloride U3 P
Bcnzpynnium bromide
Bromodiphephydramme HQ
Butetbamine HQ NJ'
Drugs Hot Usually Available in Pure Form
0 27
Carbacbol U3 P
0 36
017
Cetyltnmethyl ammonium bromide
0 09
024
Chlot^cUzme HCl UJS P
0 17
019
Chlorcsium®
010
023
Chlorpheniramine maleate U S P
017
020
CUoipromazme HQ
010
023
Comecame®
018
018
C^^melhycaine sulfate
013
C^clopeotamme HQ
036
018
016
Qdopentolate HCl
020
005
Decometbomum bronude
035
020
Dibutolme sulfate
016
017
Dichlorophenarsme HQ
035
025
Dicyclomine HQ
0 18
172 Solution Dosage Forms
Table 28 Part 2 (Continued)
Sodium QaowDE Equivalents op Drugs Not Usually Available in Pure Form
Dicth)lcarbaraazine citrate 014
Dthydrocodetoone cnobcctate HG 0 14
DihyJroh}drox}codcinone 014
Dihydromorphinone HG U^ P 0 22
Diphcnhydmmuie HG U S P 0 2S
Diphenmethanil inelhyhulfale 0 15
Dip) rone® 019
Edrophooium chlondc 0 31
Epbednne lactate 0 26
Epincphnnc HG 0 29
Erythrom>cm glucohcptonate 007
Eth^Inorcpincphnne HG 032
EvansBIueUSP 006
Feme cacodylate N F 009
Gallamine tnethiodide 008
Glucosulfone sodium 016
Glyphylline 0 12
Hcumethonium bromide 022
Hexomethonium chlonde 0 27
Hexobarbito] sodium N P 0 26
Hexylcamo HG 026
Histoloc® 051
Histamine phosphate U S P 0 25
Histidine monob) Jrochlonde N F 0 29
4 Hofflosulfanilamide HG 0 28
Hydralazine HG 0J7
H) drox) amphetamine H Dr U S P 026
lodophthalcm sodium U S P 0 17
lodopyracct U S P Oil
lodopyracct dicthylamine 012
Udocainc HG N F 0 22
Lobeline HG 0 16
Mcnadionc-diphosphate 0 25
Mcphcntcramine sulfate Ui> P 0 22
Mercaptomenn sodium U S P 0 18
Mercurophylline P 013
MemlylU^P 012
Mclhacholinc bromide 0 28
Mcthanlhcline bromide U^ P 015
McthapyrdcnellGU^P 0 19
Methoxanune HG U^ P 026
Naphazolinc HG N F 027
Naphunde sodium® 010
Ncoarsphenamine 0 40
Neostigmine bromide P 0 22
Neostigmine methylsulfate P 0 20
Nikethamide US? 018
Novaldm® 0 25
Oxophcnarsine HG P 0 24
Oxytctracycline HCI P 0 13
Pcntolinium tartrate 017
Phenanone sulfoxylate 0 33
Phcniramine maleate N F 016
Phenylephrine HCI U S P 0 32
Phenylephrine tartrate 0 19
Phenylpropylmethylamme 0 38
PiperMaine HCI U S P 0 21
Piridocaine HCI 0 24
PJaquend® phosphate 018
PramoxineHG 018
Prc^arbital calcium 0 25
Probarbital sodium N F 0J2
Promethazine HG N F 0 18
Propoxycaine HCI 0 19
pynlanune maleate U S P OIS
Quinaenne HG U.S P 018
Quinacrue methanesulfonate 0 1 1
Quimdine gluconate N P 012
Sodium folate 012
Sodium ncinoleate 0 10
Sodium sulfadimidine 0 21
StibophenUSP 018
Streptomycin calcium chlonde complex 0 20
Streptomycin HG 0 17
Succinylcholine chlonde U S P 0 20
Sulfisoxazolc diethanolamine 018
Sympocainc® HG 018
Synkamm®HCl 0 32
Synthcnale® tartrate 0 19
Tetracycline HCI U S P 0 14
Tclrahydrozohnc HG 028
Thiopental sodium U.S P 0 27
Tolazoline HG U S P 0 34
Transenune® HCI 0 22
Tnbiomoclhanol P 005
Trimclhaphaa camphorsulfonatc 010
Tnplennamine HG P 0 30
Tropacocaine HG 0 25
Trypanamide P 0 20
Tuanunoheptane sulfate N F 0 27
Uoao® 0 12
Vinbaibitol sodium 0 26
Table from Ilammarlund, E. R., and Pederson Bjcrgaard k. J Am Phans. Ass [ScL] 42 107. 1958
Specia] Soiulions 173
The use of these values will be illustrated
by prescnphon examples
1 9
Procaine HCl 2%
Nfft isotonic solution f 5 u
Smce the prescnption is m the apothecary
system, we shall assume that 18 gr of pro-
caine HCl are used E = 0 18 Therefore,
a solution with an osmotically equivalent
amount of sodium chlonde ^^ould cootam
3 2 gr of sodium chloride Two ounces of
an 0 9 per cent solution would contam 8 gr
of sodium chlonde Therefore, we need an
additional 4 8 gr of sodium chlonde to
render the prescription isotonic
2 U
Eserme salicylate 0 5%
Pilocarpine mtrate 1 0%
Sodium sulfite 0 1%
hlft Isotonic solution 30 cc
This prescription is wntten in the metnc
system and will be manipulated in that
system
0 15 X 0 14 = 0 02 Gm NaCl
0 30 X 0 21 = 0 06 Gm NaCl
0 03 X 0 57 Om NaCl
0 10 Gm NaO total
0 9% NaCl = 0 27 Gm
Therefore, 0 17 Gm additional NaCl is
needed
3 5
Epbednne sulfate
Mft Isotonic solution
0 9 X 0 23 = 0 21
The closeness of the answer raises the
quesUon of whether it is really necessary to
add the other 60 mg of sodium chlonde
Several studies have shown that the eye does
not perceive differences if the solution is
equivalent to 0 5 to 2 0 per cent sodium
chlonde ** Most authors have rccom
mended the use of 0 7 to 1 5 per cent NaQ
as the practical conccntraUon range There-
fore, It would be reasonable to omit the
addition of any further sodium chlonde to
this prescnpuon or any other which falls in
the above range
3%
30)
Sodium sulfacetamide 30 I
Sodium bisulfite { I
Water q s ad 100
Let us assume that the E value for sodium
sulfacetamide is not given m the Table and
It will therefore be necessary to estimate it
as follows
30X 023 = 69
Without further calculation, this prescnp-
tion IS obviously hypertonic Since there is
no soun» of negative sodium chlonde, it will
be necessary to compound this prescnption
as wntten with no additional salts
Most ophthalmic solutions are buffered as
well as ad 3 usted for tomcity, and the adjust-
ment of buffered coUyna wtU be discussed m
the next section
Hydrogen Ion Concentration. The normal
pH of lacnmol fluid was the subject of debate
for many years but is now known to be ap-
proximately the same as that of blood, 7 4
Thus, It might seem reasonable to buffer all
ophthalmic preparations to this value How
ever, other factors must be considered ^ For
example, the soIubOity and the stabihty of
most ophthalmic drugs are strongly de-
pendent on pH The solubility of weak acids
(eg, atropine sulfate, pilocarpme mtrate)
will decrease as the pH mcreases, and the
solubility of weak bases (e g , sodium
fluoiescein, sodium suffadiaime) vnll de-
crease as the pH decreases Many ophthalmic
drugs are amides and esters which are liable
to hydrolytic degradation The use of pres-
sure cookers for sterilization greatly mag-
nifies the stability problem If the * rule of
thumb ’ that the reactiou rate doubles for
each 10 degree nse in temperature is used,
the rate at 121 “C wiU be approximately
tunes as rapid (as at room temperature)'
Fifteen minutes at 121 °C will therefore be
equivalent to approximately 10 days at room
temperature (llie heating and the cooling
tunes will also mcrease the degradation ) As
mcDtioncd earlier (cf section on stability)
such drugs are more stable m slightly acidic
solution Solutions with a pH greater than
5 0 should probably be sterilized by filtra-
uon
174 Solution Dosogs Forms
Tte effect of pH on therapeutic activity and, where nccessaiy (c g , epmephnne,
in the e)e 15 debatable Most authors belie\e esenne), an antioxidant such as 0 2 per
that penetration of biologic membranes such cent sodium bisulfite The E values for buffer
as the cornea is accomplished by the un- solutions must always be considered when
charged spcacs of a drug Therefore, ii they arc used in compoundmg The E values
would be expected that weak acids are more for the two buffer solutions a&vc arc
E (Done acid) =04? 2 X 47 - 0^4 Gm /lOO ml
E (NaH2P04) =046 4 X 46 = I 84
E (NojHPO^) = 0 53 4 73 X = 2.50
E(Naa) = 10 4 30
8 64 Gm/ 1, 000 ml
effective at higher pH values and weak bases
at lower pH v^ucs
This particular argument becomes aca-
demic if the buffer capacity of lacnmal Ouid
IS great enough to bring the pH of instilled
solutions back to pH 7 4 immediately If this
were true, the pH of the applied solution
would have no effect on pharmacologic
activity Some workers have obtamed results
which indicate that this is true “ A recent
ubhcauon disputes these results Tolazolmo
ydrochlonde was found to be ineffective at
a pH of 5 30, although ^te effective at pH
vmues greater than 6 05 ^e author expl ains
his results with an expenment with artifiaal
lean He shows that artificial lacnmal fiuid
required H to 1 hour to neutralize added
drug The student should note that this i$ a
rate phenomenon — the buffer capacity is ade-
quate, but the return of pH to normal is
slow **
Many authors consider a nonbuffered solu
Uon of pH 5 00 (e g , 2% bone acid) to be
well tolerated Honever, others claim that
any pH less than 6 2 is disunctly tmtaung
and leads to tearing °
These remarks should alert the student to
the controversy surrounding the concept of
buffered ophthalmic soluuons Although
many different buffer systems ha%c been sug-
gested, the two which have been widely ac-
cepted are 2 per cent bone acid. pH sis S
(it IS, of course, not actually a buffer but it is
usually so named) and the Hmd-Goyon
buffer pH 6 8^
Sodium acid phorphale 4 00 Cot
(anhydrous)
Dictum phosphate 4 73 Gm
(anhydrous)
Sodium chlonde 4 30 Gm.
Distilled water, q s.ad 1,000 ml
Each solution should contain a preservative
Both of these formulations therefore are m
the isotonic range without added mcdicmal
agent This is quite useful, smee the large
maprity of dru^ arc used m such low con-
centration that ihejr addition will sliU leave
the final product within the isotonic range
with further adjustment unnecessary Excel-
lent general directions for tlic preparation
of ophthalmic prescriptions may be found m
NF xno
Viscosity Adjustment. The use of 0 33 per
cent (4 000 cps) metbylceUuIose with
1 50,000 bcozolkonium chloride has been
recommended as a tear substitute ** Methyl-
cellulose m 1 per cent conccotration may be
used to increase the viscosity of an oph-
thalmic solution in order to delay the rapid
washing away of the solution * **
Parenteral Solutions
The primary difference between paren-
teral and opbihahmc solutions is the need
for pyrogen free water m the preparation of
p^cDtcraJs Tha iS by the vse
of freshly distilled (not dciomzcd) water m
at) preparations
Many authors have noted that red blood
ccU membranes arc not scmipcrmcablc to
several salt solutions and that the i values of
some substances arc not those theoretically
predicted.* « Before preparing par-
enteral soluuons of any substance, the
ongiaal articles should be consulted.*
Pharmaceutical Solutions
The student will find it insliucUsc to read
the package inserts found m modem propn-
ctarics A few sample formulations arc given
in the following Tlic student should study
• rurther mfomuuoa on pareatcraJ* Is avail
able (a Sproitls, J B Amencan Pharmacy, 3di
ed. Chapter 12, Philadelphia. UpptneoU. 19W).
Special Solutions 175
them and attempt to understand the need for
each of the nontherapeutic agents
T^zme Nasal SoluUon®
Tetrahydrozolioe HCl 1 mg.
Benzalkomum chionde 0 02%
Disodium EDTA 01%
Certified color q s
Sodium chloride and sodium
citrate
Adjust to optimum pH with
HCl q s ad 1 ml
Digifalline Natirelle®
Chief Glycoside of Digitalis
purpurea 0 2 mg /ml
PE.G— 300 28 6%
Glycerme 43 8%
Benzyl alcohol 4 0%
Ethanol 5 0%
Water for injection \ 8 6%
Amber Ampules
Ferrous sulfate
Sorethytan Laurate
Fnut flavored vehicle
55 5 mg.
150 mg
qsad/m)
Promazine HCl
Sodium formaldehyde
sulfoxylate
Sodium metabisulfite
Sodium EDTA
Calcium chloride
Sodium acetate bufler
Sparine Injectioo®
0 75 mg
0 25 mg
0 099 rag
0 039
q $ ad 1 ml
£larfl Injection®
Amitnptybne HCl 10 mg
Dextrose 44 mg
Methylparaben 1 5 mg
Propylparaben 0 2 mg
Water for injection q.s ad 1 ml
Serpasil Injection®
Reserpine 2 5 mg
Adipic acid 10 mg
Dimetbylacetarmde 01 ml
Sodium EDTA 0 1 mg.
Benzyl alcohol 01 ml
PE.G 300 05 ml
Ascorbic acid 0.5 mg
Sodium sulfite 0 1 mg.
Water for lojecUon q s ad 1 ml
(packaged m dark bottle)
Dramandne Injection®
Dimeabydnnate 250 mg.
Benzyl alcohol 25 ml
Propylene ^ycol 2.5 mL
Water q.s.ad 5 ml
Epitrate "Ophthalmic^
1 Epinephrine bitartrate 2 %
Chlorobutanol 0.5%
Nfethylammoacetopyrocatechol HCl
Sodium bisulfite
Sodium chlonde
Dioc^i sodium sulfosuccmate
Sodium EDTA
Compazine Injection®
Prochlorperazine etbanedisulfonate 5 mg.
Sodium sulfite I mg
Sodium bisulfite 1 mg
Sodium phosphate 8 mg
Sodium biphosphate 12 mg.
CedllaDid — D
Desacetyl lanatoside C 0 2 mg,
Citnc acid 1 25 mg
Sodium phosphate 5 3 mg
Alcohol 7 4%bywL
Glycerin 15 %bywt
Water for injection q s ad 1 ml
Neo-Synephnne Injection®
Phenylephrine HQ 1 0 mg
Sodium bisulfite 2 mg
Citrate buffer qsadlmL
Sodium chlonde
Hydrocortone Phosphate Injection®
HydrocoitisoDe'21 phosphate
disodium salt SO mg
Creatinine 8 mg.
Sodium citrate 10 mg
Sodium bisulfite 3 2 mg
Phenol 5 mg
Sodium hydroxide to adjust pH
Water q s ad 1 ml
Cecon®
Ascorbic acid 10
Propylene glycol q sad 100
Tussar Syrup®
d Methorpban bydrobromide 60 mg.
Phemiamme maleate 45 mg
Phenylpropanolamine HCl 30 mg
Sodium citrate 780 mg
Otncacid 120 mg.
Chloroform 90 mg
Methylparaben 30 mg
Vehicle qj ad 30 ml
Neo*Vadrin
Pfaenylpropanolaxmne HCl 4%
Phenylephrine HCl 15%
Chlorobutanol 15%
Benzalkooium chlonde 005%
The student should be aware that texts
can only distill the results of many years of
176 Solution Dosage Forms
research and study la order to truly ap-
prcaatc the problems mv-ohed and to under*
stand more fully the subjects discussed, be
will find reading some of the original refer-
ences rewarding
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39 Martin, F M , Jr , ami Mins, J k. Aitb
Ophtal (Par) 44 561, 1950
40 hicllen, M , and Seltzer, L. A J Am
Phann Ass [Sci J 25 759, 1936
41 Menczcl, E., Rabinovitz, M, and Gold
berg, Y J Pharm. Pharmacol 12 562,
1960
42 Miller, O H J Am. Pharm Assoc Praci
Ed J3 657, 1952
43 Mims, J L. Arch Ophtal (Par) 46
664, 1951
44 Mitchell, A G J Pharm Pharmacol
14 175, 1962.
45 Moncncir, R W The Chemical Senses,
New York. Wiley, 1946
46 Moncrief, R. W Drug Cosm InJ. 84
310. 1959
References 177
47 Moore, W E J Am Pharm Ass [Sci 1
47 855, 1958
48 Mueller, \V H , and Dcardorff, D L.
J Am Pbann. Ass [SciJ4J 334. 1956
49 Mullins, J D , and Macek, T J J Am
Pharm Ass [Sci ] 49 245, 1960
50 National Formulary, ed 11, p 502 1960
51 Neidig, C P , and Burrell, H DrugCosm.
Ind 54 408, 1944
52. Patel, N IC, and Koslenbauder, H B
J Am Pharm Ass [Sci ] 47 289, 1958
53 Pisano, F D , and Kostenbauder, H B
J Am Pharm Ass [Sci] 48 310 1959
54 Pryor, J G , Apt, Leonard, Leopold, and
Irving, H Arch Ophtal (Par ) 67 612,
1962
55 Purdum.'W A 3 Am Pharm Ass [Sa]
31 298, 1942
56 Purdum, W A, J Am Pharm Ass [Sci ]
32 103,1943
57 Riegelman, S J Am Pharra Ass [Sc»]
49 339, 1960
58 Riegelman, S , and Fischer, E Z.
J Pharm, Sci 51 210, 1962
59 Riegelman, S , and Vaughan, D G , Jr
J Am. Pharm. Ass [Pract ] 19 474, 1958
60 Riegelman, S , Vaughan, D G , Ir , and
Okumoto. M Ibid 45 94, 1956
61 Riegelman, S, Vaughan, D G, Jr, and
Okumoto. M J Am Pharm. Ass [Pract]
16 742, 1955
62 Schwarz, T W , Shvcmar, N G , and
Renaldi, R. G J Am Pharm. Assoc
Pract Ed 19 40,1958
63 Scott, M F , Goudie, A. J and HuettC'
man, A J j Am. Pharm Ass [Sci ] 49
467, 1960
64 Setmkar, I , and Paterlini, M R J Am.
Pharm Ass [Sci] 49 5, 1960
65 Setmkar, I , and Temelcou, O J Am.
Pharm Ass [Sci ] 48 628, 1959
66 Soehnng, K., KlmgmuUer, O , and Neu
wald, F Arzneimittel Forsch 9 349,
1959
67 Swan, K C , and White, N G Am J
Ophthal 2S 1043, 1942
68 Swintosky, J V , Rosen, E , Robinson,
M J , Chamberlain, R. and Guanni,
J R J Am- Pharm Ass. [Sci ] 45 37,
1956
69 Theodore, F H , and Feinstcin, R R
JJ^MA J52 1631, 1953
70 Tozer, G A J Am Prof Pharm 25 30,
1959
71 United States pharmacopeia, ed 16, p 828,
1960
72 Un, N Mechanism of Antioxidation m
Lundberg W O Autoxidation and Anti>
oxidants, p l6D, New York, Interscience,
1961
73 Wesley, F J Am Pharm Ass [Pract ]
18 674, 1957
74 West, G B , and Whittet, T D J Phann
Pharmacol Trans 113 T, 1960
CEHERAt. References
S olubility
75 Hildebrand, J H , and Scott, R L. Regu
lar Solutions, Englewood CliSs, N J ,
Prentice Hall, Inc , 1962
Stability
76 Schou, S A Am J Hosp Phann J7 5,
1960
77 Schou, S A Ibid 17 153, 1960
FlaTonijg
78 Crocker, E C Flavor, New York, Me
Graw HiU, 1945
Ph^-Sical Pharmacy
79 Martin, A. N Physical Pharmacy, Pbila
delpbia. Lea & Febiger, I960
Phj-Sical Constants
80 The Merck Index, ed 7, Rahway, N J ,
Merck & Co , i960
ft lA
Chopfer 5
Liquid Dosage Forms Containing
Insoluble Matter
Harold M Beal, Ph D.*
LIQUID DOSAGE FORMS
CONTAINING INSOLUBLE
MATTER
Tv,o classes of substances — suspensioos
and emulsions — present a unique (^allenge
to the dispensmg pharmacist because of the
unstable nature of sohd ui-liquid and liquid
m liquid dispersions
Solid in liquid dispersions, classified under
the general term of suspensions and sul>>
divided in pharmaceutical nomenclature
under vanous names in the past — i c , mix*
turcs, magmas, etc. — may be considered to
mdude both pov.ders in the dry fonn to be
placed m suspension on dispensmg and
medicinal substances suspended m liquid
vehicles with or without suspending agents
Liquid m liquid dispcisions->-emuIsions—
arc defined os preparations consisting of two
immiscible liquids, usually oil and water, one
of which IS dispersed os small globules m
the other
Common problems arc present in the for-
mubtion of both suspensions and emulsions,
m that an attempt is made m each case to
overcome the effect of gravity, with its gcn>
cral problem of sedimentation of solids in
suspensions and phase separation in emul-
sions Smee compounding equipment and
stabilizing agents arc similar or identical for
both classes of preparations, this chapter dis-
cusses both, rather than in the traditional
method of considering suspensions and emul-
sions separately
The great number of medicinal agents cm-
* Associate Professor of Phamacy, School of
Phannacy, Umvcraiiy of CoouccucuL
ployed for internal or external use m a
liquid form has greatly challenged the dis-
pensing and manufactunng pharmacist be-
cause of his limitation to a few nontoxic
liquid vehicles Many of the new drugs have
poor solubility in the pharmacist's limited
supply of solvents, foremg him to turn to the
suspension or the emulsion as a dosage form
This has resulted in his investigation of the
physical*chcmical properties of such dis-
persions
PROPERTIES OF LIQUID DOSAGE
FORMS CONTAINING INSOLUBLE
MATTER
Until recently, the major concern regard-
mg an acceptable suspension or emulsion was
Its ability to remain dispersed long enough
to provide a uniform dose when taken orally,
mj^lcd or applied to the skm External sus-
pensions nccessanly required as small a
particle size as possible to elimmatc gnttioess
when applied to the skin surface
Particles settling under the force of gravity
arc considered to follow Stoke's equation
d»(p~p,)g
18 >r„
where V is the settling rate, d is the mean
diameter of the particles, p is the density of
the particles, pe is the density of the disper-
sion medium, g is the acceleration due to
gravity and 17a is the viscosity of the disper-
sion medium The apphcabiliiy of Stoke's
equation is limited to the foUowmg condi-
tions ( 1 ) The dispersion medium is of uifi-
mtcly large volume compared with the dis-
178
Particle Size in Relotion to Pharmacologic Action 179
perscd phase, (2) the dispersed phase consists
of smooth and ngid true spheres, ( 3 ) the
particles are mdependent and not flocculated,
( 4 ) the particle velocity is small, ( 5 ) there
IS no shp between particle and liquid, (6) the
particle IS large enough to be unaffected by
the kmetic motion of the suspendmg liquid
and ( 7 ) electncal effects between particles
and the hqmd are neghgible
It IS immediately apparent that pharma-
ceutical suspensions and emulsions, because
of the high concentration of the dispersed
phase, do not meet the above cntena
Higuchi^* has modified the approach to
creammg and settling by treatmg the suspen-
sion and the emulsion as systems of fiuid flow
throu^ a packed bed
Heterogeneous dispersions are stabilized
by treatment of two factors of Stoke’s equa-
tion — ^particle diameter (d) and the viscosity
of the dispersion medium (170) An attempt
IS made to retard settlmg or creaming by re-
duction of the particle size of the d^persed
phase to the smallest diameter feasible withm
limits of the equipment available and by in-
creasing the viscosity of the dispersion
medium by the addition of various hydio-
coUoids and other agents The problem is
compounded by the fact that very small par-
ticles possess a great deal of energy lb a
system of high concentrauon of dispersed
phase this results m considerable particle-
particle mteraciion m an attempt to reduce
the surface free energy, lowering the total
surface by particle agglomeration
Martm*‘ considers another approach to
the stabilization of suspensions, m addition
to the use of protective colloids, 1 e , the
application of surfactants to reduce the mlec-
facial tension between the particle and the
liquid He also discusses the use of dispersmg
or deflocculating agents Examples of the
latter are the Darvans (R T Vanderbilt
Co ), Daxads (Dewey and Almay) and the
Marasperses (Marathon Corp ) The Daxads
and the Darvans are polymerized oigamc
salts of the alkjl aryl type represented by the
following formula
Na+ -O5S • CHj • Aiyl • SO,- Na+
The Marasperses are calcium and sodium
lignosulfonatcs Deflocculating agents are not
classified os true surfactants and do not
greatly lower surface tension They seem to
be ateorbed on the surface of the particle
throu^ polar forces, greatly increasmg the
negative charge on the particle and resultmg
m particle particle repulsion
Caking vs Flocculation
Consideration must be given to the even-
tual result of the settlmg of particles m a
suspension, smee most solid m-hquid dis-
persions do not remam evenly dispersed for
long periods of tune The suspension must
be prepared m such a manner that the solids
are redistributed with ease by shakmg If
the dispersed paitides form a compact mass
m the bottom of the contamer the suspension
IS said to have “caked ” The resull may be a
mature which is impossible to administer as
an even dose
Haines and Martin^* carried on a
study of caking m pharmaceutical suspen-
sions They classify particle interaction m
two ways, physical and/or chemical reactions
fonmog strong bonds between particles re-
sulting m “caking*’ or weakly bonded re-
actions of the van der Waal s type leadmg
to * flocculation ” Their study indicated that
a suspension m a state of fine deflocculated
particles leads to caking In some cases, com-
monly used suspendmg agents and elec-
trolytes exaggerate caking The authois sug-
gest that controlled flocculation, rather than
dcQocculation, will prevent caking m some
pbannaceutjcals The study recommended
the use of a nontoxic flocculating agent, to-
other with a viscosity-increasing agent, to
stabdize and flocculate suspensions
A classic example of clay foimauon is
shown by a mixture of hydrated magnesium
oxide and sodium bicarbonate in an aqueous
suspension. Magnesium carbonate crystals
slowly form and fuse to a compact mass,
which will not resuspend. Replacing the
magnesium oxide by magnesium carbonate m
the onginal compounding prevents this for-
mabon
PARTICLE SIZE IN RELATION TO
PHARMACOLOGIC ACnON
Numerous mvesUgators have substantiated
the observation made by Flippm et dL,* in a
study of microctystalline sulfadiazine vs
ISO Liquid Dosage Forms Containing Insoluble Matter
US P sulfadiazine, in which the greater rela-
tive rapidity of absorption of the micro-
crystals was showTi m human subjects by
evaluatmg scrum blood Icsels Grccngard
and Woolcy^ evaluated the effect of admin-
istering sulfur m a colloidal form and also
in the form of a 100 mesh powder It was
reported that the colloidal form was absorbed
at a rate three to four times as fast as the
pow der form of the drug
Several authors'* have reported
that betur absorption of drugs from oint-
ment bases consistently occurs on reduction
in size of the particulate matter dispersed in
the base
Investigators cognizant of the importance
of fine particles have devised improved
methods for obtauung these matcnals
Essentially, the processes can be classified
into two broad categones The first mvolves
methods based on a reduction m size of a
preformed crystal powder or agglomerate
TIic second entails a condensation or an
agglomeration of smaller discrete units to
form particles of specific size The first
method IS used more often at present for
producing particles of low micron size, but,
because of many diQlculucs inherent to this
process, condensation methods arc bemg m-
vestigated
The rcducuon processes can be subdivided
in the followmg manner (a) those pro-
FiQ 71 Stuncvani microoizcr
ccdurcs in which the solid to be treated is
dispersed m a liquid medium and aaed on
in that medium, and (b) those methods in
which the materials arc processed in the diy
form.
Most equipment for dry pulverization of
substances to provide particles m the micron
range operates on procedures that are quite
sio^ar The material to be pulverized is ex-
posed to streams of high velocity air The
solids arc carried mto the violent turbulence
by sonic or supersonic velocity streams In
this turbulent environment the particles
collide with one another and with the walls
of the chamber to yield low micron particles
The Sturtevant Micronizcr* is an example of
equipment of this type (Fig 71)
Ihc wet or the suspended solid procedure
IS the method most often used ui presenpuon
practice to prepare suspensions Smee pre-
scription laboratory equipment is available
for this purpose, it will be discussed under
sohd m liquid dispersions (p 181)
A recent approach to the production of
particles of low micron size has been through
controlled ciystallizauon Crystallizauon is
essentially a two-phase operation which is
initiated by the formation of nuclei or grams
and IS concluded with subsequent groi^ of
nuclei to macro size By talang a super-
saturated soluuon and causing rapid crys-
tallizauon dunng high-speed sUmng and a
sudden drop in temperature small particles m
the range of 5 microns and below can be
produced Tliesc fine crystals can be resus-
pended for oral, topical and parenteral ad-
mmisirauon Recent mvcstigation by Alkm-
son €C a ! ' and Kraml et al ** on the effect of
gnscofulvm paruclc size on blood levels in
man has resulted m a halving of the oral dose
of gnscofulvm by control of particle size be-
low S microns
SOLID-IN-LIQUID DISPERSIONS
(SUSPENSIONS)
In the preparation of suspensions m pre-
scnpiion pracucc the pharmacist is somewhat
limited m the modificauons which be can
make to produce a stable and elegant
product, being confined by the manner m
* Sturtevant Mill Company, Dovton 22 , Mavs
Solid In Liqu d Dispersions (Suspensions) 181
Fig 72 Hand homogenizer
which the prescription is wntteo However
there are two meAods which he can use for
suspension stabilization (a) reduction ot the
size of the dispersed particle either by break
mg up aggregates or reducing mdividual par
tides to a finer state of subdivision and (b)
mcreasing the viscosity of the dupersion
medium by the use of suspendmg agents
Equipment for Panicle Sue Reduction
Small scale equipment is now available to
the pharmacist m mcreasing quantities
Apparatus for the production of the sheanng
force necessary for breaking up aggregates
of particles was once confined to the mortar
and pestle Most of the equipment available
IS equally applicable to the stabilization of
emulsions by particle size reduction
One useful compounding tool is the hand
homogenizer (Fig 72) consisting of a
piston which forces the liquid through an
orifice closed by a brass pm held in place by
a sprmg The pressure exerted by hand
pumpmg the piston causes the aperture to
open and allow the liquid to pass Consider
able shearing action results in the deaggtom
eration of solids and the reduction of globule
size m emulsions
The general household use of the blender
(Waring Blcndor Osteiizcr etc.) for food
preparation has resulted m a general reduc
tion in the cost and the prescnption depart
meat has gamed a mixing umt of high effi
cicncy for the dispersmg of sohd aggregates
Blendor Head i| 1
Fig 73 Waring Blendor wilh polylron
assembly
and the reduction of globule size In addi
tion the Warmg Blendor has a bomogenizmg
attachment ideal for prescnption use The
Polytron Assembly* (Fig 73) consists of a
3 bladed rotor runmng withm an 8 slotted
stator Opeiatmg as a centnfugal pump the
rotor blades dnve matenal at high speed
against the shearing edges of the stator slots
ITie large number of shearmg faces acceler
ales particle size reduction for fast dispersing
and homogenizmg The umt possesses the ad
vantage of high shear and low capacity per
nutting Its use m prescription practice
Certain of the colloid mills available can
• Will Sc enlific Inc Rochester 9 N Y
Fig 74 Charlotte ND 1 Stannary model
coUoid m II with rotor removed to show
rotor stator arrangement
182 Lquid Dosage Forms Conlo nmg Insoluble MoHer
be used for stabilization of suspensions and
emulsions m quantities small enough for
prescription compoundmg The Chariotte
ND 1 • mill with a capacity of 1 to 35 gallons
per hour (Fig 74) is an example of this type
The disadvantage of a colloid mill lies in its
rather high cost for a prescnption depart
mcnL
The ball and pebble mill may be used for
particle size reduction of solid in lic^uid dis-
persions However, the time required for
processing of the suspension may often
climmate its use m extemporaneous presenp-
uon compounding
Suspcmioos Without Suspending Agents
Some solid in liquid dispersions may be
written for and prepared without a suspend
log agent, depending on the density of the
dispersed particles, ihcir tendency to floccu-
late or caie and how well they are uetted
by the dispersion medium The following
prcscnptioos arc wntten examples of this
type
1 Q
Liquor carboais detergeos 1 OmI
Zinc oxide tSOGm
Starch 18 0 Cm
Gl)cena 28 Oral
Liinewaterqs ad 900ml
M Ft loiioa
Sig. Apply hs.
2. 1)
Resorcinol 1 SO
Sodmm biboratc 0 82
Starch 3 75
Calamine 3 75
Alcohol ad 60 00
M
Sig Apply to acne q d
3 n
Magnesium sulfale ^ J
Light magnesium carbonate 3iss
Aq menth pip q s. ad 5 tv
M ftsusp
Sig. 3ilLs
4 n
Magnesium truilicate 2.4 Gm.
Light magnesium carbonate 2.4 Cm
Sodium bicarbonate 2.4 Gm.
* Oumkolloid Laboraioncs Inc., Garden Cly
Park, N Y
BcUadoona tincture
30ml.
Peppemunt water ad
600inl
hf fLnustura.
Sig. 5 u Vi hr pc
l>
Zinc sulfate
40^9
PoUssa sulfurata
22*9
GI}cenn
3%
Stronger rose water
359
Purified water q s
M /htal loLPOO
Sig Apply to face b i d
This IS a concentrated White Lotion (LoUo
Alba) Dissolve the zinc sulfate m enough
water to make 54 ml and the sulfuratcd
potash m enough water to make 30 ml Filter
each and slowly add the sulfurated potash
solution to the zme sulfate solution with con-
stant trituration m a mortar Add the glycenn
and the water and mix well Dispense in a
Wide mouth bottle
In most cases of this type, improvement
may be made by the addition of a suspend-
ing agent to mcrcasc the viscosity of the
preparation, and the physician may be con
tacted for such changes Hand homogeniza-
tion or treatment m a blender will fur^cr in-
crease the elegance of the product
StabilizaliOn by Increasing Ibe Viscosity
of tbc Dispersion Medium. In addition to
deagglomcration of solids and reduction of
particle size to prevent settling of a suspen-
Sioo, certam viscosity increasing agents are
available for compounding use Since this
represents the easiest approach to suspension
stabilization, it is the one most often used.
The requirements for an agent of this type
are (a) that it have no therapeutic action
Itself in the concentration used, (b) that it
be relatively chemically inert over a wide
pH range, (c) that it form a viscous disper-
sion in low concentrauon, (d) that it not
change in viscosity over a period of storage,
and (e) that it either be soluble in water or
Swell m iL
This group of suspending agents u clossi-
fled as protccusc colloids, capable of form-
ing a film around the dispersed particle
and/or imparting high viscosity to ^e dis-
persion medium. In addition to retarding
Qoccubuon of the dispersed particles, pro-
tective colloids reduce the sedimentation
Solid (n Liquid Dispersions (Suspensions) 183
rate by increasing the viscosity of the dis-
persion medium
Rheolo^c Properties of Solid>in-Liquid
Dbpersions. With the exception of suspen-
sions m which there is a very large per-
centage of dispersed phase compared with
dispersion mechum, the flow properties may
be considered essentially those of the agent
used to mcrease the viscosity of the system
Proper selection of a suspendmg agent or a
mixture of suspendmg agents, according to
the flow properties of their aqueous disper-
sions, will simplify the production of an
acceptable suspension
Viscosity-mcreasmg agents, with the ex-
ception of newtonian materials such as
glycerm, sucrose solutions, etc , are classified
as non newtoiuan substances, ue , those ma-
terials which do not follow Newton’s equa-
tion of flow Figure 75 shows the flow char-
acteristics of various materials
A newtoman liquid (Fig 75, A) flows
when acted on by any force, the rate of shear
bemg directly propomonal to the shearing
stress, as shown by the straight line extending
to the ongm Non newtoman substances ex-
hibit flow that has been classified mto several
^es, plastic flow, thixotropic Sow, pseudo-
plastic Sow and dilatant flow
A hquid that exhibits plastic flow (Fig
75, B) does not flow unUl the applied shear-
mg stress exceeds a minim um value This
minimum shearing stress is designated as the
yield value
Plastic flow IS frequently associated with
an mtemal structure which is temporarily
destroyed by stirrmg or shakmg, but reforms
on standmg A substance that exhibits this
flow pattern is said to be thixotropic (Fig
75, (^) and the property is designated as
thjxotfftpy The clays bentomte, hectorite
and Veegum* are thixotropic substances
These^ substances form a gel structure on
standmg but become liquid on shakmg? thus,
they have many applications m suspension
stabilization
Most of the natural and the synthetic by-
drocolioids exhibit pseudoplastic flow (Fig
75, D), these mclude tragacanth, methyl-
cellulose, sodium carboxymethylcellulose, the
al^ns and Carbopol 934 1 A substance
which shows this property flows more readily
as It is sheared and begms to flow at low
sbearmg stress, but no part of the curve
exhibits Imeanty As a result, the viscosity
of pseudoplastjc materials can be expressed
ad^uately only by a plot of the entire con-
sistency curve
Dilatant flow is exhibited by suspensions
• R- T VaaderbiJt Co , New York 17, N Y.
tB P Goodncb Cheoucal Co, Cleveland 15,
Ohio
Fio 75 Characteristic flow curves of various substances (A) New-
toman substance (B) Plasuc substance (C) Thixotropic substance.
(D) Pscudoplastic substance (E) Dilatant substance (F) Pseudo-
ptakic substance with thixotrophy (Martin, A. N Physicd Phannacy,
Philadelphia, Lea & Febiger)
184 Liquid Dotage Forms Conloining Insoluble Matter
uith high conccntrauoos of solids, such as
paints, mks, pastes, etc These substances
show increased resistance to flow with in-
creased shearing stress (Fig 75, E)
Figure 76 illustrates ideal flow patterns of
non nett toman substances This ttould sel-
dom be shoun in actual substances For ex-
ample, some pscudoplastic materials do show
thixotropy due to breakdown of structure
with shear (Fig 5, F)
Classification of Dispersion Stabilizers.
Protective colloids arc classified in several
wa)s, one of which is their general division
into similar chemical classiflcations, as
follows
\ l^atural plant and animal h^drocoUoids
A Plant derivatives
B Animal denvatn cs
2 Modified plant derivatives
3 Clajs
4 S)7itheUc h)drocolloids
Plant Hydrocolloids
Acacia is the dned gummy exudation of
Acacia Senegal and various other acacia trees
throughout the world It is often designated
in commerce as gum anbic." It is a ma-
ture of die calcium the magnesium and die
potassium salts of orabic acid. As with other
natural h)drocolloids, the viscosity of acacia
solutions is ailcctcd by the age of ^e tree
from which the gum is collected, amount of
rainfall storage condiuons, pH, addition of
salts etc Acacia solutions retain their vis-
cosity through a pH range of 4 to 10 Because
of the low viscosity of acacia dispemons,
they arc less used as suspension stabilizers
than are some of the other plant h)drocol-
loids However, acacia is used as ancmulsify-
mg agent and will be discussed further under
emulsions The following prcscnptions illus-
trate the use of acacia as a suspension
stabilizer
6 I)
Heavy magnesium oxide
3u
Magnesium sulfaie
3vu
Gl}ccnn
3»
Acacia muedage
Peppermint water ad
5«‘
M
Sig. 3sstid
11
Precipitated sulfur
4 8Gin.
Camphor 0 4 Gra.
Acacia, fine powder 2.4 Cm
Lime water 60 0 mL
AquaRosaeqs ad 120 0 ml
M ft lotion.
Sig Apply to allcclcd area q 4 hr
Tragacantli is the dned exudation of
Astragalus g«mmi/cr and other species of
Astragalus The ^gum consists of 60 to 70
per cent of bassorm and 30 to 40 per cent
of iragacanthm In water, bassonn swells to
form a gel and tragacanthin a colloidal dis-
persion Tragacanth owes its cfTccUyeness to
Its capacity to hjdrate to form a'viscous
dispersion when placed in water Although
tragacanth hydrates vety slowly, its rate may
be increased by the shearing action of rc
pcated hand homogenization of the disper-
sion Tragacanth dispersions exhibit maxi-
mum viscosity at a pH of S, showing a rapid
drop m storage m a range below pH 4 5 and
above pH 6 "* »
8 n
Camphor spinl 6 0
Alcohol ' 6 0
Precipitated sulfun 3 6
Tragacanth, fiae powder 0 9
Purified water ad 60 0
M
Sig Apply to face night and morning ^
Mix the precipitated sulfur with the trag-
acanih and gradually add about 40 ml of
water with constant tnturatjoa Mix the
camphor spirit and the alcohol and add this
mixture to the sulfur suspension Add enough
purified water to make 60 ml
The following prescription illustrates the
use of tragacanth as a viscosity-mcreasmg
agent and a film former m a podiatnc prep-
aration
9 n
Camphor gr vu
Menthol gr xiv
Tragacanth 5 ss
Glyccnn o us
Alcohol 3 us
Amaxanlh solution 1% Tn.xii
Purified water ad 3 m
M ftloUon.
Stg. Apply to feet q 4 hr uL dicL
Solid In Lquid Dispersions (Suspensions] 185
Dissolve the camphor and menthol m the
alcohol Triturate the glycerm with the trag-
acanth to a smooth paste Add the alcohol
solution, the amaranth solution and the
punhed water m divided portions to make
the final volume
Algins. The term designates the water*
soluble derivatives of alginic acid, obtamed
by extraction from species of kelp Algunc
aad is a Imear polymer of anhjdro-jS D-
mannuronic acid The most important de*
nvatives are the sodium, the potassium and
the ammonium salts and the propylene glycol
ester Carehil control of manufacturing con-
ditions has made available a senes ot prod-
ucts ranging from low to high viscosity Since
the algimc acid salts are amomc m character,
they show their greatest viscdsity stability at
pH 5 and above When propylene glycol*
alginate was made available, the range of
usefulness was extended to pH ranges below
pH 5
Sodium algmate, the derivative most fre-
quently used, IS soluble m water and insolu-
ble m alcohol Low coocentratioos of alcohol
produce higher imtial viscosity values than
does water alone, while higher concentrations
(30 to 40%) precipitate sodium algmate
from aqueous dispersions *
Other natural plant b)drocoUoids are used
to a lesser extent than are acacia, tragacanth
and the aigms and are not encountered nor-
mally m prescription practice Karaya, the
dried exudation of StercuUa urens, is used
to a great extent in the food industry and to
a lesser extent in pharmaceuticals Its mam
application is as a bulk laxative Locust bean
gum and guar gum — very similar in prop-
erties — are used to some extent m pbaima-
ceuticals Canagecmn, the dried extract of
certam species of seaweed, is also used to a
limited extent as a suspending agent and a
stabilizer of emulsions
10 B
Zjqc oxide
Starch
Glycerm
So^um alginate, mcd vis-
cosity
Liq calc bydrox
Aq Ros qs ad
M ft.
Sig Apply as duected.
* Kelcoloid S, Kelco Company, San Diego. CaUL
Tnturate the sodium algmate, the starch and
the zinc oxide together with the glycerm to
form a paste Gradually add the lime water
and, finally, the rose water to volume
Preservation of Natural HydrocoUoid Dis-
persions. The natural hydrocoUoids are very
subject to decomposition due to micn>organ-
isms Thus, when they are used as suspend-
ing or emulsifymg agents, certam of the
preservatives must be used Among the ac-
ceptable ones are a phenylmercunc mtrate
1 50,000, thimerosal 1 50,000, sodium
benzoate 1 S per cent and combmation of
meihylparabcn 0 2 per cent and propyl-
0 02 per cent
Anixul Hydrocolloids
The hydrocoUoids derived from animal
sources, i e , gelalm, egg yolk and casein, are
used pnncip^ly as pnmaiy emulsifiers or
stabili^rs m emulsification and wiU be dis-
cussed m this chapter under emulsions
Modified Plant Derivatives
(Cellulose Derivatives)
The ceUulose denvatives have become im-
portant as viscosity-mcreasmg agents because
they possess ceiiam properties that the nat-
urad hydrocoUoids do not share The syn-
thetic cellulose derivatives are produced
imder chemical control o! raw materials and
reaction product, thus, reproducible results
m usage are more likely, m contrast to nat-
ural gums whose quality is subject to the
vagaries of nature Furthermore, they are
free from insoluble substances and other
matter (morgamc salts, etc ), resulting m a
clearer dispersion
MclhylceUuIose. By treatment of ceUulose
with alJtyl halides su^ as methyl chlonde a
senes of ceUulose ethers may be obtamed —
the metbylceUuIoses * Although they are
available in viscosity types from 15 centi-
poises to 4,000 centipoises (the absolute
viscosity of 2% aqueous dispersions at
20* C), two viscosity types — 1,500 centi-
poise and 4,000 centipoise — axe most often
used in pharmaceutic^ Mcthocel HG is
the designation for a mixed methyl and
hydroxypropyl ether of cellulose Melhyl-
c^ulose IS soluble m cold water and insolu-
ble m most of the common organic solvents
* Methoec), Dow Chemical Compaoy, MidlaoU.
Michigan.
36Gm
3 6 Cm.
30ml
06 Cm.
300m]
600mi
186 liquid Dosage Forms Contoining Insoluble Matter
MetbylccUulose differs from most hydro-
colloids in that its dispersions gel on bentmg,
while those of other hydrocoUoids gcl on
cooling As the temperature approadies
SO” C , the gcl point of the mctb)lcclluJoses,
the outer layers of water molecules which are
attached to the metbylccUulosc molecule
break away ^Vhen enough of the attached
water molecules are lost from the polymer
cham, the solution is transformed mto a gcl
This phenomenon is reversible on coolmg
Metbocel HG has a gel pomt 10 to IS** C
higher than Mclhocel
Dispersion of methylccUulose presents
sometlung of a problem, and, as a result, it
IS very often used m the form of a mucilage
m prcscnption coropoundmg However, there
arc three ways m which it can be bandied
One method is, fint, to mix the mcthyiccl-
lulose thoroughly with one third of the re-
uircd amount of water as hot water ($0-
0° C ), then, to add the remainder of the
water as cold water The second method is
to mu the mctbylccUulose with a small
amount of alcohol or glycerin before adding
the cold water to prevent lumping If methyl-
cellulose IS to be used m a formulation con-
taming other dry logredieols, it may be
blended with these ingredients prior to mu-
ing with water
11 n
Coal tar solution
30
Glycerm
IJ
Aqua Hamamelidis ad
300
M
Sig Pat on abraded area
and oUow to
dry
When 10 ml of a 2 per cent Methocel HG
dispersion is thoroughly mixed with the coal
tar solution and the other ingredients added
gradually, a stable dispersion results
12 U
PbenaceUn 5 Is*
Glycenn 3i
MethylccUulose 400 cps., 3*0 sol Svu
Aromatic elixir ad 3 ui
M fL Mist.
Sig. 3iq 4hr forpain.
Triturate the phcnacctin with the glycerm,
add the methylccUulose dispersion and mix
Gradually add the aromatic cluir to volume
Sodium carboxymcthylccUuIosc is pre-
pared by treating highly purified cellulose
with alkali and subsequent reaction with
sodium monochloroacetate It is a fibrous or
granular powder, light cream to white m
color, and is readily soluble m hot or cold
water As opposed to methylccUulose, the
viscosity of sodium caiboxymetbylccUulose
(carboxy methylccUulose, CMC) decreases
With mcrcasmg temperature Its dispersions
fall wiihm the pH range of 6 5 to 8
Carboi^ethylccUulosc has a good toler-
anoi to ctbanol, with up to 40 per cent of
ethanol permissible m low concentration dis-
persions If It 15 Duxed with mmcrol acids, the
tree acid of carboxymethylceUulosc is formed,
and precipitation results when a cntical ex-
cess of the acid has been produced
CarboxymethylceUulose is available m
three viscosity grades low viscosity— 25 to
50 cps m 2 per cent dispersion, medium vis-
cosity— 400 to 600 cps m 2 per cent dis-
persion, and high viscosity— approximately
1 400 cps m 1 per cent dispersion
13 Ti
Banum sulfate
350 OGm.
CMC70, Prem Grade,
low viscosity
200Gm.
Dioctyl sodium sul/osue
cioatcsol 1%
1600ml
Flavor
50inl
Sacchann sodium
05 Cm
Sorbitol soluUoQ 70^
1500ml
Purified water to make
1,000 0 ml
M
n
Sulfadiazine
6 OOGm.
Sulfamenmae
6 00 Cm.
Sodium lactate
36 00 ml
Saccharin sodium
0 70Gm
Tr lemon peel
3 60 ml
CMC med vise, sol
qs ad
12000 ml
M
Sig SOq 4hr
Powder the sulfadiazmc and the sulfamcra
ztne m a mortar, add the sodium lactate, the
saccharin sodium and the CMC solution with
constant tnturation
hLcrociystalliac ccUuIose,* which is pre-
paid by severe aad hydrolysis of ceUulose,
* Aviccl, Amencaa Viscose Corporation, hlum*
Hook, Pa.
Soiid'In-Uquid Dispersions (Suspensions) 187
can be dispersed in water to form vis-
cosity thixotropic dispersions that are stable
over long periods. Early mvestigation* indi-
cates that mlcrocrystalline cellulose will prove
to be a very satisfactory snspendmg a^nt-
Clays
The clay minerals of the montmonllonite
structure have long been used as stabilmog
agents for suspensions, due to their abili^ to
form thixotropic dispersions of high viscos-
i^. The suspending properties of these clays
are due chieSy to then singular latllcelike
crystalline structure. The three clays most
often used are bentonite, hectonte and
Veegum.*
Bentonite (US.P. XVI) is described as a
native, colloidal hydrated aluminum silicate,
pale buff or cream colored, free from gn^
with a slightly earthy taste. The best grades
of bentomte usually swell m water to 15 times
their dry volume, forming a thixotropic dis-
penion m low concentrations. As a suspend-
mg agent, a 2 to S per cent dispersion of
bentomte is used. Bentonite is anionic in
character and is markedly inSuenced by pH,
showing maximum viscosity in the alkaline
range. In additloc, incompatibilities may be
expected witlL cationic substances such as
benzalkonlum chloride, gentian violet, ibia-
n^e hydrochloride, etc.
Electrolytes change the character of
bentonite dispersions in many respects, de-
pending on the kind of electrolyte, the con-
centration of bentonite and the concentration '
of electrolyte relative to bentomte. Mono-
valent ions have the least effect, and trivalent
the greatest effect An excess of either cations
or anions results in coalescence and floccula-
tion of bentonite particles.
15. O
Menthol
023
Phenol
0.45
Liq. carb. det
. 9.00
Talc
1800
Glycerin
13J0
Bentomte
3 60
Purified water ad
9000
M.
Sig.: Apply tld.
Mix the powders with the glycerin in a
• Veegum F and Veegum HV, R. T. Vanderbilt
Co., New York 17, N. Y.
mortar, dissolve the menthol and the phenol
in the coal tar solution and add to the glyc-
erin paste; gradually add the water with
constant trituration to volume.
16. B
Zinc oxide
12 Gm.
Talc
12 Gm.
Glycerin
12m].
Alcohol
8 ml.
Magma bentomte
48 ml.
Purified water ad.
120 ml.
M.
Sig : Leinei's Lotion.
Triturate zinc oxide, talc, glycerin
and alco-
hoi together; gradually add the
bentonite
magma with constant tnturation and, finally,
the purified water to volume.
Hectonte, t a member of the montmoril-
lomte group of days, is closely related to
bentomte. As a result, its behavior is very
sumlar and it may be used in the same man-
ner. Certam properties, especially its greater
rate of hydration and its white color, give it
some advantages over bentonite.
Veegum may be considered to be a highly
purified form of bentonite. The purification
procedure removes silica, grit, nonhydrating
materials, etc. Veegum is supplied in ^e form
of while flakes (Veegum HV), which swell
on hydration as does bentonite. Its behavior
as to pH changes, alcohol and electrolytes
closely follow that of bentomte. Veegum dis-
persions are thixotropic as are those of ben-
tonite. Veegum is generally used in concen-
trations of l.S to 2 per cent
17. n
Prepared chalk
3.6
Gm.
Saccharin sodium
0018 Gm.
Veegum HV magma 3%
30.0
ml.
Cinnamon water
240
ml.
Purified water ad.
60 0
ml.
M.
Sig.: Chalk Mixture. 15 ml. a c.
Mix the Veegum magma with the cinnamon
water, and add enou^ of this mixture to the
saccharin sodium and the prepared chalk in
a mortar to fonn a smooth paste. Gradually
incorporate the remainder of the diluted
magma and, finally, enough purified water
to make 60 mL
t Available as Macaloid, Inerlo Company, 1489
FoUom Saa Ftanosco, f^if-
188
Liquid Dosage Forms Conloining Insoluble Matter
AU of ihc clay dispersions may be prepared
m the same manner However, it most be
remembered that bentonite takes a longer
period of time to hydrate and will take as
much as 24 hours to reach its maximum vis-
cosity When the dry powder IS used, the clay
IS triturated with the insoluble substances in
a mortar and the vehicle is added a little at
a time until the final volume is reached \Vhen
a magma of the clay is used, it is usually m
the concentration of 2 to 5 per cent Ben-
tonite magma is prepared by sprmkling the
powder on hot purified water and allowing
to stand for 24 hours with occasional stirring
Magmas of all tlie clays may also be pre-
pared by adding the clay to hot punfied water
with rapid sturing, as in a blender
Since the cla)s will support growth of
microorganisms under certain condiuons, a
preservative is generally considered desir-
able, «c. a meth>lparabcn (0 2%)-propyl-
araben (0 02^%) combination or sodium
enzoateO 1 percent
Synthetic Hyorocolloios
In Uie attempt (o overcome some of the
disadvantages of natural products, especially
the lack of purity and uniformity of h)dro>
colloids of plant ongm, many s)nthctic poly-
mers have ^cn prepared Of these a caiWxy
vin)l pol)Tncf* of high molecular weight has
had tne most extensive use Supplied as a
white powder in the acid form,, it is neu-
tralized with alkali and exhibits its greatest
viscosity at a pH range of 5 to 10 Carbopol/
934 may be used in both internal and exter-
nal preparations The following kaolin pcctm
presenpuon shows an example of the use of
Carbopol 934 os a suspending agent
18 It
Kaqim
t! 66
Pectin
026
Carbopol 934
018
Sucaryl sodium
OM
Pcppcrnimt oil
0 35
Mciiiyi salicylate
035
Sodium caibonatc to neutralize
DwUllcd water ad
6000
M
It must be remembered in the use of Carbopol
that Its neutralized gels tend to undergo oxi-
• n p Gocxinch Chemual Co^ Cevclaod 15,
dative degradation when exposed to light.
Schwarz and Lcvy“ reported this loss of vis-
cosity and aitnbutcd it to the presence of
trace metals Therefore, when Carbopol is
used as a suspending agent, the suspensions
should be protected from light or contain
antioxidants or EDTA to complex trace metal
ions
Carbopol is also quite sensitive to small
amounts of electrolytes, showmg a marked
decrease in viscosity in its neutralized aque-
ous dispersion Preservatives which are lomc,
such as benzoic acid, sodium benzoate, etc.,
can cause the decrease m viscosity
Ionic Behavior of Hvdrocolloids
In employing viscosity increasing agents,
the chemical reactivity of these substances
should be takciv into account Most of the
suspending agents used are antonic in nature
(acacia, tragacanih, sodium alginate, karaya,
carragecnin, sodium carboxymcih)lceUuIosc,
Carbopol 934, bentonite, hcctontc and Vee-
gum) Mcthylcellulose, microcrystalline cel-
lulose and pTop)tlcnc glycol alginate are non-
ionic Nakashima and Miller,*^ m a study of
tome incompatibilities of suspending agents,
showed that the use of some anionic suspend-
ing agents resulted in the prccipitauon of or-
ganic cationic substances such as thiamine
hydrochloride, neomycin sulfate, bcnzal-
komum chloride, etc , with the rcsulung pos-
sibility of inactivation of the substance Tins
was especially evident with the clays and in-
dicates the need for care m selection of a
viscosily-incrcasmg agent to be combined
with cationic substances
LIQUID-IN-LIQUID DISPERSIONS
(EMULSIONS)
The pharmacist encounters the emulsion
system in his dispensing pracucc more often
than he may realize and shpuld be thoroughly
familiar with emulsion technology He prot^
ably will be concerned less with emulsions
to be taken internally than with external oil-
m-water or water in-oil lotions used both for
their emollient action and as viscous liquid
earners for insoluble medicinal agents
It is assumed that the student is thor-
oughly familiar with the thconcs of emulsi-
fication and the terminology of this class of
pharmaceuticals However, it may be wue to
Lqutd In Lquid Dispersions (Emulsions) 189
review some o£ the features of an emulsion
system Although an emulsion may be con-
sidered as a two-phase system consisting of
two immiscible liquids, one of which is dis-
persed throughout the other in the form of
globules, from a practical standpoint a third
component — the emulsifying agent — must be
added to stabilize the heterogeneous disper-
sion This third substance onents itself at the
interface, thereby aclmg as a bndge between
the immiscible hquid pair It reduces the
interfacial tension between the two and forms
a film around the dispersed globule, prevent-
ing or retardmg coalescence of the mtemal
phase Emulsion technology, as far as the
pharmacist is concerned, involves a knowl-
edge of the types of emulsions which he will
encounter, plus an awareness of the myriad
of emulsifymg agents which he has at bis dis-
posal for producmg satisfactory oil m-water
and water m-oil emulsions
Ihe pharmacist must realize that the sta-
bility of an emulsion may be improved if
(a) the particle size of the internal phase is
decreased as far as possible, (b) the optimum
ratio of oil to water is used, and (c) the vis-
cosity of the system is mcreased
Globule Sue. As the globules of the to-
temal phase are reduced to a sue approach
mg the colloidal range (under 5 microns),
they are influenced by brownian motion, this
helps to keep the globules m a uniform dis-
persion This IS accomplished by shearing
action rcsultmg from efficient and prolonged
trituration m a mortar, the passing of the
emulsion through a hand homogenizer or a
colloid null or muung it m a blender
Phase-Volume Ratio. The volume of the
mtemal phase compared with that of the
external phase (phase-volume ratio) will m-
fluence the characteristics of an emulsion
Generally speaking, the most stable emulsions
have an mtemal phase occupying between
40 and 60 per cent of the emulsion As the
percentage of mtemal phase mcrcases the
viscosity of the emulsion nscs due to the
packmg of the globules of the mtemal phase,
preventmg free movement m the external
phase When the concentration of the inter-
nal phase approaches 80 per cent, there is
mechanical crowding to such an extent that
the emulsion usually has the consistency of
a paste
Viscosity. The pharmacist is limited m the
changes which he can make m the phase-
volume ratio of an emulsion, however, he
may mcrease stabihty by adding certam m-
gredients to mcrease the viscosity of the ex-
ternal phase To raise the viscosity of the
extemd phase of an oil m water emulsion
he must add a substance which is soluble m
or miscible with water and, also, has the ca-
pacity to mcrease viscosity The polyethylene
gjycols, cellulose ethers, natural and synthetic
gums and clays have been used successfully
as viscosity mcreasmg agents If the pharma-
cist wishes to raise the external phase vis-
cosity of a water-m-oil emulsion, he must
add to the system a substance which is solu-
ble m or miscible with the oil phase and will
increase its viscosity Among the substances
which have been used for accomplishmg this
m water-m-oil emulsions are viscous oils,
waxes, fatty alcohols and fatty acids
Classification of Emulsdjmg Agents.
Emulsifying agents may be classified mto
three mam groups
1 Natural emulsifying agents
A Those from vegetable sources
a Carbohydrates such as acacia,
tragacanlh, chondrus and pectm
b Those derived from cellulose
B Those from animal sources
a Gelatin, egg yolk and casern
b Wool fat and cholesterol
2 Fmely divided solids
3 Synthetic emulsifymg agents
A Amomc
• B Cationic
C Nomomc
Natural Emulsifying Agents from
Vegetable Sources
The natural emulsifymg agents from vege-
table sources all have some of the same fea-
tures, as they are all carbohydrate denva-
Uves, glycosidclike and amonic m nature, all
produce oil m water emulsions under normal
circumstances and are sensitive to high con-
centrations of alcohol or salts They are dif-
ferentiated by the way m which they act as
emulsifiers lliose which reduce mtcrfacial
tension and form a tough mechanical film
around the dispersed phase are considered
to be * true” emulsifiers, those which func-
tion by mcreasmg viscosi^ to the extent of
preventmg creammg and coalescence are con-
sidered * quasi" emulsifiers
)90 Liquid Dosage Forms Contoin ng insoluble MoMer
Acacia uas discussed under suspcndiog
agents previously m the chapter In general.
It )iclds good, stable and palatable emulsions
of low viscosity Other gums, such as traga>
canth, agar or pccUn, ore often added in
small quantities to increase the viscosity of
thes)stem
Acacia emulsions may be made by the wet
gum (English), the dry gum (Continental)
or the bottle method (with volatile oils)
(Sec p 198 ) The ratio of gum to oil vanes
from 1 part of acacia to 2 parts of volatile
oH to 4 parts of hxed oil The following pre-
scnption illustrates the use of acacia as an
emulsifying agent
19 0
Kaolin lOSGm
Aluminum hydroxide OA Gm
Mineral oil ISOmJ
Acacia 4 S Gm
Peppermint water ad 90 0 ml
M ft emulsion.
Sig. Onctablcspooofulqd
Triturate the liquid petrolatum with the
acacia Add 9 ml of pcppermiat water and
form a primary emulsion Mix the Icaolm and
the aluminum hydroxide with the remainder
of the peppenmnt water and add slowly to
the nucleus
20 n
01 ncini
3i5nil
Acocu, in fine powd.
8 1 Gm.
Tr vanilla
23inl
Syrup
ISOml
DtsL water ad
900ml
M ft emulsion
Sig. Three tablespoonfuls at bedtime.
Triturate the acacia with the oil Add 16 ml
of water all at once and form an emulsion
Incorporate the s)Tup, the tioctuie and the
remamder of the water m small amounts with
tnturauon.
Tngacanth emulsions may be made by
cither the wet gum or the dry gum method,
keeping m mind that 0 1 Gm of tragacanth
IS required where 1 Gm of acaaa was used
When the wet gum method is used, a muct'
lage IS made of 1 part of gum to 20 parts of
water Tragacanth emulsions are stable but
tend to be coarser than those made from
acacia Passmg through a hand homogcmzcr
materially improves their particle siae and
appearance The following liniment uses
tragacanth as the emubiher
21 B
Liquid petrolatum 18 00
Bergamot oil JO
Lavender oil JO
Sodium benzoate 43
Tragacanth 1 80
Distilled water ad 12000
M ft emulsion
Tnturate the liquid petrolatum with the traga*
canth until smooth, add 38 ml of water all
at once and moke an emulsion Dissolve the
preservative m 12 ml of water and add
gradually Add the oils and enough distilled
water to make 120 ml This emulsion d&>
mands a larger amount of tragacanth than
normal because the low percentage of hquid
petrolatum mcreascs the viscosi^ require-
ment.
Agar IS employed to some extent as an
auxiliary cmulsther m liquid petrolatum cmul*
sions To mcrcase viscosity it is used m the
amount of 1 per cent of the total volume of
the emulsion The general procedure is to
prepare an emulsion with acacia, water and
oil and then add a 2 per cent agar mucilage
to this emulsion
Chondrus. In itself, Chondrus is not very
adaptable to prcscnption use because of the
difficulty m preparing the mucilage from the
plant However, its refined dned extract,
conageenm, is available under the names of
Sea Kern* and Kraystayf m a variety of
types, depending on their ultimate use These
substances arc rather sensitive to electrolytes
and hydrolyze at low pH values They will
tolerate up to 20 per cent of alcohol before
gcUing
Pectin IS often used alone or m combma-
tioa with acacia as an emulsifier ^Vhen em-
ployed alone, 0 1 Gm. of pccUn is used to
replace 1 Gm of acacia in the emulsion.
When used to mcrcase the viscosity of acaaa
emulsions, a concentration of approximately
1 per cent of the final cmubion volume is
employ cd
*5ea Plant Corporation, New Bedford Mass.
t Phenu Foods Company, Queago 90, IIL
Lquid In Liquid Dispersions (Emulsionsl 191
22 B
Ltqmd petrolatum
500
Pectm
1 0
Syrup
LOO
Methyl salicylate
04
Punfied water ad
1000
M ft emulsion.
Mix the pectin and half of the hqtiid petio-
latum in a mortar, add 25 ml of punfied
water all at once and triturate until an emul-
sion IS formed Allow to stand for 10 min-
utes and contmue tnturation until white and
creamy Add slowly, with tnturation, the re-
mamder of the liquid petrolatum, the syrup,
the methyl salicylate and the rest of the pun-
fied water
Algms. Sodium alginate, discussed eadiec
m the chapter, is classed with tragacanth and
pectm as one of the substances which emulsi-
fies prmcipally by mcreasmg the viscosity of
the mixture Satisfactory emulsions may be
obtamed with 50 per cent of oil with the
use of about I per cent of sodium algmate,
medium viscosity Propylene glycol alginate*
may be used m prescriptions of the foUowuig
type
23 9
Paraldehyde 15 0
Syr Pruni virgmianae 75 0
Kelcoloid S 06
M ft. emulsion.
Sig 15 0 ml b.s
Form a mucilage with about 15 ml of the
wild cherry syrup and the propylene glycol
algmate and gradually add the paraldehyde
m mcreasmg amounts, with constant tritura-
tion, until emulsification is complete, then
add the remamder of the wild cherry syrup
Other Emulsifiers. At vanons tunes sub-
stances such as honey, malt extract, hconce
extract, etc , have been used as emulsifymg
agenU Smee they are httle used, they will
not be discussed here
Natural Emulsifiers Derived
FROM Cellulose
The modified celluloses are generally
ihou^t of as agents for the suspending of
solids but may be used successfully in many
emulsion formulations They possess the ad-
• Kelcoloid S, Keleo Company, San Diego, Calif
vantages over the natural gums of higher
punty and less sensitivity to changes m en-
vironment pH, concentration of electrolytes
and the presence of mold or bacterial or-
ganisms
Methylcellulose has been described m
some detail under suspensions It may be
used both as a primary emulsifymg agent and
as an auxiliary emulsifier to mcrease the vis-
cosily of emulsions Excellent emulsions can
be obtamed with mmeral oil and cod hver
oil, using methylcellulose as the primary
emulsifier “ A dispersion of the meihylcel-
lulose IS made, placed m a mortar and the
oil added m small amounts with constant
trituration
24
Castor oil ^ i
Methocel HG 2% Sol g l
Vanflla Tr TTt xx
M fL emulsion
Sig Jssbs
Make a 2 per cent Methocel HGf dispersion,
place m a mortar and gradually add the oil,
with constant tntuiation, to fonn as emul-
sion Addthefiavor
Sodium Caiboxymethylcellulose (CMC)
may also be used as a primary emulsifier but
IS generally used with other emulsifiers to
mcrease viscosity
Emulsifying Agents from
AND.UL Sources
Egg yolk, egg albumm, casein and con-
densed milk have been used occasionally as
emulsifymg agents m pharmaceuticals How-
ever, gelatm remams the one which is used
frequently m the production of oil m-watcr
emulsions, especially with mmeral ofi.
Gelatin. The US P distmguishes two types
of gelatm ' Gelatin derived from an acid-
treated precursor is known as l^pe A (Phar-
magel A) and exhibits an isoelectnc pomt
between pH 7 and 9, while gelatm denved
from an alkali treated precursor is known as
Type B (Pbarmagcl B) and has an isoelectnc
pomt between pH 4 7 and 5 ”
Pbarmagel A is generally used m an acid
solution m the range of pH of 3 to 3 5 At
this pH it IS positively charged and is mcom-
t Dow Chemical Company, Midland, Mich.
1 92 liquid DoMge Forms Containing Insoluble Matter
paublc lAith ncgauvcl) charged h)droco!Iotds
such as acacia, tragaconth or agar Phaimagd
B IS used in a pH range abo\c ils isoelectric
point In this range, it is negatively charged
and IS compatible with the negatively charged
h)drocoUoids
When gelatin is used as an emulsifier, it is
impossible to male a satisfactory emulsion
with mortar and pestle Homogenization or
treatment with a colloid mill is necessary In
prescription practice the hand homogcnizcr
has proved to be quite satisfactory
Gelatin may be used in a low concentra*
Uon — in the area of 1 per cent — of the total
emulsion volume The procedure consists of
adding most of the water in the formula to
the gelatin, heating to 98 100“ C and stir*
nng until the gelatin is dissolved When cool,
the gelatin solution the od and the other
ingredients ore mixed roughly and passed
through a hand homogcnizcr several times
25 II
Pharroagel A
Tartaric acid
Svrup
Vanillin
Alcohol
Liquid petrolatum
Purified water ad
120Gm
70 mg.
n ml
5 mg.
72 mL
60 ml
120 ml
M ft emulsion
Sig Ssshj
Add the Pharmagcl A and the tartanc acid
(to bnng pH to acid range) to 36 ml of
water Heat at boilmg for S to 10 minutes
until all of the gelatin dissolves Cool to
50“ C., add liquid petrolatum, syrup, flavor,
alcohol and enough purified water to make
120 ml Pass through the hand homogenizcr
several times
All of the previous substances discussed
as emulsifying agents have certain things us
common all normally are soluble or dis>
pcisible m water and are oil in water cmulsi-
ficn In addition, if emulsions arc to be
stored for any period of time, preservatives
must be added The ones most used are so~
dium benzoate, benzoic acid, alcohol and the
parabcos
Wool Fat and CholcsteroL Wool fat and
Its mam active mgrcdient arc used more
often as water in-oil emulsifiers m ointments
and creams or emollients Wlicn they are
used m liquid preparations of the lotion tj-pe.
they are generally auxiliary emulsifiers
Finely Divided Solids
Many finely divided solids, especially those
which arc hi^Iy h)dratcd in dispersion, will
form very stable emulsions, usually of the
oiI-in*watcr type Examples of compounds
of this type which will onent at tlic interface
between oil and water arc bentonite and the
other cla)s, magnesium h)droxtdc, aluminum
hydroxide and magnesium tnsilicatc Some-
times the emulsion may be prepared by agi-
tatmg the magma of the compound with the
oil 10 a bottle Usually, the magma is placed
in a mortar and the oil added m small
amounts with constant tnturatioo Hand
homogenizatioQ or treatment in a blender
greatly improves this type of cmukion The
followmg prescriptions arc examples
26 n
Liquid petrolatum
F E cascara 3 j
Magma magnesia ad 3
M ft emulsion.
Sig 3ssh4
Place the magma magnesia in a mortar Add
the liquid petrolatum, with constant tntura-
uoo, in small amounts until all has been
emulsified Add the flujdcxtract Mix. If nec-
essary, pass through a hand homogcnizcr
27 «
Cottonseed oil
300
Oleic acid
06
Aluminum hydroxide gel
150
Puniied water ad
60 0
M ft emulsion
Place the aluminum hydroxide gel m a mor-
tar, gradually add a mixture of the oil and
the oleic acid with constant trituration until
completeJy emuhtBed. Add the punBcd water
tovwume Hand-bomogenize if necessary
28 n
Camphor (X3
Menthol OJ
Phenol 0 6
Olive oil 24 0
Bentonite magma ad 60 0
Sig. Apply to Itching area.
Liquid In Liquid Dispersions (Emulsions) 193
Tnturate the three eutectic substances to-
gether and add the olive oil Place the ben-
tonite magma (35 mi ) m a Wedgwood mor-
tar and gradually add the oil solution m small
amounts, with constant trituration, until
completely emulsified Hand homogenization
greatly improves this preparation
Synthetic Emulsifying Agents
A few of the substances that belong to a
large group classified as surface active agents
or surfactants have emulsification also as one
of their applications The usual method for
groupmg these compounds is according to
their behavior m solution Most of the sur-
factants ionize m water, and either the anion
or the cation is responsible for the surface-
active properties If the anion is the surface-
active po^on of the molecule, it is termed
an anionic surfactant If the cation is the
surface active portion of the molecule, it is
called a cationic surfactant If it is a molecule
which possesses surface active properties but
does not ionize, it falls into the classification
of nonionic surfactants In the following sec-
tions those compounds which are used prm
cipally as emulsi^mg agents will be discussed
Anionic Emulsifying Agents
In this group appear three important types
soaps, s\]^atM compounds and sulfonated
compounds All have one characteristic m
common — their mcompatibility with acids,
catiomc surfactants and caUons which will
react with the anion to form an insoluble
compound
Soaps may be considered as the reaction
products of fatty acids above Cj4 with alka-
Ime substances, i e , KOH, NaOH, NH4OH,
Ca(OH)2, Zn(OH)2, Mg(OH)2 or an or-
gamc amin e such as tne&anolamme When
they are used as emulsifying agents, the re-
action forming the soap usually takes place
during the preparation of the emulsion
Alkali Soaps (Monovalent) These
substances produce oil in water emulsions,
unpart atkafim ty to the finished preparatioa
(pH 9 to 10) and are seldom used m inter-
nal preparations because of their bitter taste
and laxative action. In the presence of ex-
cessive amounts of multivalent cations such
as calcium 10 ns an msoluble soap is precipi-
tated In an acid medium the alkali soaps
form the free fatty acids Smee the free fatty
acids are feeble emulsifymg agents, this usu-
ally results m breaking of the emulsion The
following formula is a lotion type utilizing an
alkifii soap as the emulsifier
29 I?
Stearic acid 3.5 Gm
Glycerin 8 0 Gm
Potassium hydroxide 0 2 Gm.
Alcohol 8 0 Gm
Lanolin 2 0 Gm.
Purified water 78 3 Gm
The procedure used m compounding this is
a standard one for emulsions of this type
The water soluble substances — m this case
the glycenn, potassium hydroxide, alcohol
and water — are heated together to about
70® C The fat-soIuble ingredients — ^lanolm
and stcanc acid — are heated to the same tem-
perature, the two solutions are mixed and
allowed to cool to room temperature with
stirring
This type of lotion base is used less often
than others because of its alLahnity and tend-
ency toward skin nntation and sensitization
Metallic Soaps (Divalent) This group
results from the reaction of fatty acids
(whether alone or as a component of a fixed
oil) with zme hydroxide, magnesium hy-
droxide or calcium hydroxide Neither the
zinc soap (zinc stearate) nor the magnesium
soap (magnesium stearate) is used as an
emulsifier However, the calcium soap is one
of the emulsifiers most used m dermatologic
practice
Calcium oleate produces water m-oil emul-
sions, imparts alkahmty to the finished emul-
sion and 15 limited to external use because
of the characteristic taste of soaps It is sen-
sitive to an acid medium which liberates the
free fatty acid but has a higher acid tolerance
than ihe alkah soaps
Emulsions usmg a calcium soap as the
emulsifymg agent are prepared by mixing
calcium hydroxide solution with a fixed oil
m equal portions or with the oil m excess
If the acid value of the oU is too low, the
addition of a small amount of oleic acid often
will produce a satisfactory emulsion This
emulsion base may be used as a vehicle for
msoluble solids The foUowmg are lotion-
type dermatologic prescriptions of record
194 Lqv d Dosage Forms Contoin ng Insoluble Matter
30 n
Pulv calanuoe
Zinc oxide
Olive Oil
Lime water aa 30
M
Sig. Apply locally b i d. ct
Shake the lune water and the obve oil m
a 2 Qoz. bottle until a creamy emulsion re-
sults Pbcc the powders m a mortar and add
the prepared w/o emulsion with tnturauoo
31 U
Pulv calamine
Zine oxide aa 6
Sol calc, hydroz. 25
Olive oil 9
Puntied water ad 50
hL
Sig. Locally ut diet
Since the volume of lime water exceeds that
of the oil (which will be the external phase),
first mix the full amount of olive oil with an
equal \olume (9 ml ) of lune water Agitate
uiiul the emulsion forms Place the powders
ui a monar add the remainder of the Ume
water and 16 ml of distilled water, then the
w/o emulsion Mix thoroughly
Soaps OF OkgamcAmises Several of the
organic ammes have been used to form soaps,
however, iricthaoolamme is the one used in
many lotion bases ^Vbcn reacted with steanc
or oleic acid, the soap that is formed acts as
aa excclltat od va 'Hater esnMiaificT U pro-
duces a slightly alkaline cmubion, in the
range of pH 7 S to 8 Like other soaps, tt is
mcompaUblc with acidic substances and
acidic solutions The procedure for prepar-
ing emulsions contauucg tnethanolammc
soaps IS the same as that for the alkali soapS
Menthol
0 04Cii>
Steanc acid
2.40 Gal.
Cetyl alcohol
1 20 Cm.
Wool fat
0 80 Cm*
Liquid petrolatum
4 00 mL
Tnclhanolamine
I 20 mi
Water
Perfume q s.
SSOOmL
M etSig. Back Rub Lotion (Peter Bent
Bngbam Hospital)
Heat the menthol, the steanc acid, the cetyl
3 alcohol, the wool fat and the liquid petro-
2. latum to 70® C Dissolve the tnethanolammc
m the water and beat to 70® C Mu the two
solutions StiruntucooL
33 D
Hydrous wool fat 20 0 Gm.
Steanc acid 2 0 Gm.
Light liquid petrolatum 1 0 0 ml
Tnelhanolanune 0 8 ml
Rose water qj ad 100 0 ml
M ft loUOD.
Sig. Lanolm Lotion
Heat the wool fat, the steanc acid and the
b^t bquid petrolatum to 70® C Dissolve the
tnethanolammc m the rose water and heat
to 70® C. Mu the two solutions Stir until
cool
It IS intcrcstmg to note that triethanolamme
soaps have an HLB value m the range of 12,
which explains why they have been used so
successfully as cmulsihers for bquid petro-
latum (required HLB is about 12) (For
discussion of HLB see p 195 and TaUe 29 )
Sultatcd Compounds. Many surfacUnts of
this type arc available They arc produced
by sulfating a long-cham alcohol and makmg
the alkab or amme salt. Sodium lauryl sulfate,
composed of a muturc of sulfatcd alcohols
with lauryl alcohol the prmcipal one, has
been used m pbarmaccuut^ for the past few
years as an oil in-water emulsiiicr It has the
advantage over soaps of bemg less sensitive
to aads and compaulile with colciun salts,
smcc calaum lauryl sulfate is not water m-
soluble When used by itself, sodium lauryl
sulfate forms emulsions of rather poor stabd-
ity Therefore, it is employed with stabilizers
such as cetyl or stcaryl alcohol Sodium lauryl
sulfate has been avoided by dermatologists,
who consider it a primary imlant to the skin.
TTic foUowmg formula mcludes sodium lauryl
sulfate os the cmulsibcr
34 U
Cetyl alcohol Z4Gm.
Light liq petrolatum 19 2 m]
Sodium lauryl sulfate 0 6 Cm.
Punfiedwaterad 1200ml
M ft emulsion.
Uquid'ln>L!quId Dispersions (Emulsions)
195
Heat the ce^I alcohol and light liquid petro*
latum to 70® C., dissolve the sodium laufyl
sulfate in the water and heat to the samg
temperature. Mix and stir until cool. This
may be used as a stock lotion base.
Sulfonated Compounds. Dioctyl sodium
sulfosuccinate* is die major representative
of this group of sulfonated surfactants. It is
used both as a wettmg agent and as an emul-
sifier in pharmaceuticals.
Cationic Emulsifying Agents
The cationic surfactants may be used as
oil-in-water emulsifiers. However, because of
their superior bacteriostatic properties they
are seldom used as emulsifying agents. Benz-
alkonium chloride is representative of this
group of compounds.
Noniomc Emulsifying Agents
The nonionic surfactants used in pbanna^
ceuUcals are complex esters, etben or esler<.
ethers of alcohols. They possess the advan-
tage over anionic and catlomc agents of
stability over a wide range of pH. Most non-
ionics can be made by taking practically any
hydrophobic compound wUch has in its
structure a carboxy, hydroxy, amido or amino
group with free hydrogen attached to the
nitrogen and reacting it with ethylene oxide.
Furthermore, the properties of each com-
pound can be changed considerably simply
by changing the molar portion of ethylene
oxide, that Is, by changmg the length of the
polyox) ethylene chain. Most of the nonionlcs
are viscous liquids or soft pastes. The ethylene
oxide type accoxmts for 80 to 90 per cent of
all nonionics used.
The HLB System. With the development
of the nonionic emulsifiers a great amount of
interest was taken in more exact methods of
determining whether an emulsion remained
stable or not and whether the proper amount
and type of emulsifier was bemg used. Giif-
fin®* ® assigned to the respective components
of emulsion systems a vdue indicating their
relatively lipophilic (nonpolar) or hydro-
philic (polar) characters. This value repre-
sents the ratio between the lipophihc portloa
* Aerosol OT, American Cyanamide Company.
New York 20, N. Y.
Table 29. “Required HLB” Values for
O/W Emulsions of Common
Ingredients*
Add, stearic . .
. . . 15-18
Alcohol, cetyl
13-16
Alcohol, steaiyl
13-16
Isopropyl esters
9-13
Lanobn, anhydrous
10-12
Oils
Vegetable
6-10
Mineral
10-12
Petrolatum
7-11
Waxes
Beeswax
8-12
MicrociystaUine
9-12
Paraffin
8-11
•The Required HLB of any material is bkely
to vary sLgbtly with the source of the material, the
concentraiion desired and the method of prepara-
tion, and should be verified against your own in-
gredients at your own desu’ed concentration and
with your own manufacturing technic.
Matenals that are surface acUve, such as fatty
acids, fatty alcohols, etc , uben used at high coa-
centraljoiu. wilt likely require a higher HLB.
The Required HLB for making W/0 emulsions
of any material will be in the range of 3 to 8t for
soIubiluatioD m water, m the range of 10 to 18.
From Guide to the Use of Atlas Sorbitol and
Surfactants lo cosmetics, Allas Chemical Indus-
tries, Inc., WtlffliDgton, . 1962.
of the molecule and the hydrophilic portion
and is called the hydrophile-hpophile bal-
ance (HLB).
Each emulsifier and major component of
an emulsion was assigned an HLB value of
from 1 to 20. Although higher values are
known, most surfactants fall below 20. The
higher the HLB value of an emulsifier the
more the polar portion predominates, and
the lower the value the more the nonpolar
portion predominates. It has been found that
water-in-oil emulsions are formed when the
emulsifiers are in the range of HLB 3 to 6,
while oll-in-water emulsions are formed from
HLB 8 to 18. Substances with low HLB
^ues are predominantly oQ-soIublc while
those with high HLB values are predomi-
nantly soluble or miscible in water.
Use of the HLB System. The HLB value
of the oil phase of an emulsion, i.e., oHs,
waxes, etc., must first be considered to de-
196 Liquid Doioge Forms Containing Insoluble Mottcr
Table 30 HLB Values op Some Selected Emulsifying Agents
Chemical or Generic Name
Trade Name
HLB
Soibilon Trioleate
Span or Arlacel 85*
1 8
Sorbitan Tnstcoratc
Span 65*
21
Sorbilan Scsquiolcate
Arlacel 83*
37
Gly eery 1 Monostearate
38
Sorbitan Monooleate
Span or Arlacel 80*
4J
Sorbitan Monostcorate
Span or Arlacel 60*
47
Glyecryl Monoslcarate
(ScIf-cmulsifying)
Aldo 28>
SS
Sorbitan Afonopalmitate
Span or Arbccl 40*
67
Acacia
80
Sorbitan Monolaurate
Span or Arlacel 20*
86
Gelatin
98
Pt^yoxydhyleTicSorbiiQn Tndede
Tween 85 •
no
Polyethylene Glycol 400 Monostcorate
11 6
Triethanolamine Olcatc
120
Polyoxyethylene Sorbitan Monostcaralc
Tween 60*
149
Polyoxyethylene Sorbitan Mono-olcate
Tween 80*
15 0
Polyoxyethylene Sorbitan Monopalmitate
Tween 40*
156
Polyoxyethylene Sorbitan Monoburate
Tween 20*
167
Sodium Olcate
180
Sodium Lauryl Sulfate
above 20 0
* Atlas Chemical Compao) Wilmington 99. Delaware.
tGl)CO Chemicals Corp New York 1, N Y
tenntae \shat will be the matching HLB o(
the emuisi/ier or emulsifier blend rc<;uircJ to
produce a stable emulsion Many of the sub*
stances m the oil phase base already been
assigned HLB values and may be determined
from available tables Table 29 lists some of
the Required HLB" values of common m*
grcdicnts of emulsion formulae
As an example of the use of the HLB sys-
tem the following fonnula is given t
Z^rquid perrobtum
35^
Wool fat
Cetyl alcohol
l'^
Emulsifier
7*^
Water
and an o/w lotion vehicle is desired The
percentage composition of the oil phase is
35^ + + 1*0 = ST'p and its required
HLB for o/w emulsification can be calcu-
lated as follows
Requued
HLO
Liquid Petrolatum ~ 94 6*0 X 1 2 = I i 4
t S« footnote to Table 29
WoolPal =i= 27«X10= 03
Ccljl Alcohol =-^= 27SI X 15a 04
Estimated required HLB of emulsifier 12 1
Therefore, an emulsifier or a combuiation
having an HLB range of 11 to 13 probably
Will be satisfactory
Table 30 shows some of the HLB values
of some emulsifying agents
There ore many other surfactants for which
the HLB values have been detemuned Once
the required HLB value of the oil phase has
been determined, on emulsifier or a blend of
emulsifiers may be selected of approximately
that HLB For Atlas emulsifiers charts arc
available giving HLB values of various
blends
In the formula given with Table 29, with
a required HLB value of 12 1, a sin^e emul-
sifier such as polyethylene glycol 400 mono*
stearate might prove satisfactory hfore often
a blend of two emulsifiers of similar struc-
ture, one with a high HLB value and the
other with a low HLB value, is chosen If, in
the above case. Tween 80 (HLB-15) and
Arioccl 80 (HLB-4 3) were selected the
proportion of each could be determined by
Liquid In Liquid Dispersions (Emulsions) 197
alligation This would give 78 parts of Tween
80 to 29 parts of Arlacel 80, or 5 per cent of
Tween 80 and 2 per cent of Arl^l 80
TTiere are many noniomc emulsifiers avail-
able, but the pharmacist will find that he en-
counters a relatively low number m emulsion
compoundmg
Gl>col esters consist of reaction products
when a glycol (glycenn, propylene ^ycol,
diethylene glycol, polyethylene glycol, etc )
reacts with a fatty acid — ^usually, steanc acid
With the exception of the polyethylene glycol
stearates, they are rather poor emulsifying
agents when used alone If a small amount
of an amomc surfactant such as sodium stea-
rate or sodium lauryl sulfate is added, they
become efficient oil m-water emulsifiers Two
of the group are used m pharmaceuticals
glyceryl monostearate, self-emulsifymg and
polyethylene glycol 400 raonostearate
Glyceryl Monostearate S E This mix-
ture serves as an emulsifier in many phar-
maceutical and cosmetic emulsions Because
It depends for its emulsifying effiaeocy on
the blend of nomomc amomc emulsifiers, it
has the incompatibilities of the amomes, i e ,
sensitivity to an environment of low pH
When used m liquid preparations, glyceryl
monostearate S £ is present as a coemubifier
along with amine soaps, etc An acid stable
self-emulsifymg glyceryl monostearate con-
taining a small amount of a nomomc emulsi-
fymg agent of high HLB is available as
Arlacel 165* for use in lotion formulas coo-
taming acidic salts
35 U
Cetyl alcohol
5%
Arlacel 165
5%
Sorbitol solution
5%
Water
85%
PreservaUve q s
M ft lotion base 120 ml
Heat the cetyl alcohol and the Arlacel 165
to 70® C , heat the sorbitol soluuon and the
water to the same temperature Mix and stir
until cool
Polyethylene Glycol 400 Monostea-
rate The polyethylene gl) col esters may be
used not only as nomomc emulsifiers but also
as suspendmg agents They are found in
• Atlas Chemical Company, Wilmingtoa 99,
Delaware.
many cosmetic lotions m conjunction with
amomc emulsifiers such as tnethanolamme
stearate **
36 Cleansing Lotion
1
Steanc acid
2 OGmu
2
Liquid petrolatum
150ra!
3
Isopropyl raynstate
2 0 ml
4
Polyethylene glycol 400
mooostearate
lOOGm.
5
Lanolin
5 0Gm
6
White wax
SOGm.
7
Propylene glycol
SOml
8
Tnethanolamme
I OmI
9
Preservative
OlGm
10
Punfied water q s ad
100 Oral
Mix and heat ingredients 1 through 6 to 70
to 75® C , dissolve 7, 8 and 9 in the water
and heat to the same temperature Add the
aqueous solution to the oil solution and stir
uniformly to room temperature
Sorbilan Esters. Although there are many
nomomc emulsffiers available which are satis-
factory for use m pharmaceuticals, the
Tweens* and the Spans* have had the most
application
The Spans and the Arlacels are prepared
by esterification of sorbitan with various fatty
acids Table 30 shows their chemical com-
position <The Arlacels are a highly punfied
grade of the Spans, mtended for pharma-
ceutical and cosmetic use
The Tweens arc denved from Spans by
treatment of the nonesterified hydro:^ groups
with ethylene oxide to form polyoxyethylene
side chains Chain length can be controlled
to gtve surfactants of varying polaraUes
Tween 80 is official m USP XVI as Poly-
sorbate 80
37 It
Zinc oxide
Talc
Lanolin
Peanut oU
Alum acetate sol
Polysorbate 80
Punfied water ad
M
Sig Burow’s Emulsion
12 0Gm
12 0Gni
12 0Gm.
48 0ml
2.4 ml
2.4 ml
120 Oral
Heat the lanolin, the peanut oil and the poly-
sorbate 80 to 60® C Mix well and cool to
• Allas Chemical Company, Wilmington 99,
Delaware
193 bquid Dotage Form* Containing Inmluble Matter
room temperature Mix t\ith the zme oxide
and the talc m a mortar Add the alummum
acetate solution followed by the \^atcr with
constant trituration
38 n
Castor oil 45 0 ml
Span 80 63 ml
Tween 80 (0 67'v soL) 387ml
To make 90 0 ml
M. Sig Castor Oil Emulsion.
Mix the Span 80 and the castor oil Place
the Tucen 80 solution m a mortar and add
the Span>castor oil mixture m small propor-
tions with constant trituration.^*
General Preparation of Emulsions
The pharmacist must be able to prepare
emulsions extemporaneously using the mortar
and pestle, together with whatever other
small-scale equipment he may have at his
disposal In general when working with the
gums, he uses one of three methoth of prep-
aration
Dry Gum Method (Contmenlol Method)
This method mvoUcs the preparation of a
concentrated emulsion or nucleus of oO,
acacia and water by the following procedure
The acacia and the oil arc placed u a diy
Wedgwood or porcelain mortar, m the ratio
of 4 parts by volume of hxed oil to 1 part by
weight of acacia. When the acacia is thor-
oughly distnbutcd throughout the od, 2 parts
by volume of water arc added all at once,
followed by rapid trituration until the emul-
sion IS formed This nucleus is tnturated for
St feast 5 minutes, then the additional in
grcdicnts arc added Water soluble ingrcdi
cnis should be dissolved in w-ater and added
to the nucleus in small amounts with constant
tnturaiion Insoluble substances should be
hocly powdered and triturated with the nu-
cleus Alcohol should be diluted with water
and added m small quantities Oil soluble
substances arc dissolved m the od before
the nucleus is made Finally, the cmubion is
tramferred to a graduate and brought to
volume withwatcr
Wlicn tragaconih or pcctm are used in
place of acacia Ko die amount of each Is
required The ratio for fonmng the nucleus
becomes 4 2 0 1 mstcad of 4 2 1 With Im-
seed od or liquid petrolatum the ratio of od
to acacia is often a 3 1 ratio, mabog the
primary emulsion or nucleus a 3 2 1 ratio
Wet Gum Method (English or American
Method), This procedure invoUes the prep-
aration of a mualage of acacia with water,
usually m the same ratio as is used in the dry
gum method. A smooth muedage is made
by tnturatmg 1 part by weight of acacia to
2 parts by volume of water If tragacanth
or pcctm IS used, the ratio of gum to water
becomes 1 to 20 If the gum is a fine powder,
It may be wetted with a small amount of
glycerin or aAaatof Co pretenC Jianpuig wJien
Uie water is added
After the muedage is made, the od is added
in small increments with constant trituration
until all IS emulsified The nucleus is now
triturated for 5 minutes and dduted as de-
scribed imdcr the dry gum method. If, durmg
the addition of the od to the mucilage, the
Viscosity of the emulsion becomes too high,
small amounts of water may be added to re>
turn to the ongmal viscosity
Bottle Method The bottle method is
merely a vanaiion of the diy gum method,
used with volatde ods One part by weight
of acacia is thoroughly mixed with 2 or 3
parts by volume of volatile od by shaking
m a bottle Two parts by volume of water
are added all at once and the shabng con-
tinued imlil the emulsion is formed Other
u^edicnls and the remainder of the water
are added in small quantities with constant
shaking
PRESERVATION OF LIQUID
DOSAGE FORMS CONTAINING
INSOLUBLE MATTER
Molds, yeasts and bactena find the aque-
ous phase of suspensions and emulsions a
fine medium for growth For this reason ore-
servatives must be added to both solid in-
liquid and liquid m liquid dispersions which
are to be stored for more than a few days
Benzoic acid (0 1 to 0 2% ), sodium ben-
zoate (0 1 to 02%), alcohol (5 to 10%),
pbeo)Imercuncnitrateandacctate(l 10,000
to 1 25,000), phenol (0 5%), crcsol
(0 5%), chlorobutanol (0.5%), soibic acid
References
199
(02%) and the cationic quaternary am-
monium compounds (1.10,000 to 1 50,000)
have been used as antibactenal preservatives
with varying degrees of success
The most popular preservatives, because
they are active against bactena, yeasts and
molds, have been the parahydrojybenzoic
acidesters butylparahydroxybenzoate (bulyl-
paraben 0 02%), methylparahydroxybenzo-
ate (methylparaben) andpropylparahydro:^-
benzoate (propylparaben) A combmation
of methylparaben 0 2 per cent and propyl-
paraben 0 02 per cent seems to be the mix-
ture of choice
In the use of preservauves, consideracon
must be given to the possibihty of a reaction
occumng between the substance used as a
preservative and the suspending agent or the
emulsifier that may inactivate the preserva-
tive The result may be the formation of an
mactive complex or an lomc reaction
It has been shown-® that complex forma-
tion takes place between methylcellulose and
the parahydroxybenzoic acid esters Barr and
Tice® reported the growth of micro-organisms
m the presence of surfactants containing
polyether groups A large number of non-
lomc surfactants used m pharmaceuticals
belong to this class These substances also
tend to form complexes The mvestigators
reported that soibic acid 0 2 per cent proved
to be a satisfactory preservative
With the use of polymenc substances —
natural and synthetic — as suspending and
emulsifymg agents, care must be taken to
select a preservative for a particular system
to avoid possible mactivation of the pre-
servative
PACKAGING, DISPENSING AND
STORAGE OF LIQUID DOSAGE
FORMS CONTAINING INSOLUBLE
MATTER
All suspensions and emulsions are heter-
ogeneous and should be dispensed with a
“shake well” labeL They should be stored
m a manner to prevent freezmg or exposure
to hi^ temperature If they are not sensitive
to light, they may be dispensed m clear glass
When suspensions and emulsions are viscous,
wide-mouth bottles should be used. It is often
advantageous to package dermatologic pre-
scriptions m polyethylene squeeze botUes
REFERENCES
1 Atkinson, R M , Bedford, C , Child, K. J ,
and Tomicb, E G AnUbiotics and
Chemotherapy 12 232,1962
2 Barr, M , and Tice, L F J Am Pharm
Assoc (Sci ) 46 442, 445, 1957
3 Battista, 0 A , and Smith, P A Ind and
Eng Chem 54 20, 1962
4 Bellinger, von Mane, and Munzel, K.
Pbaim actahelv 34 79, 1959
5 Fleming, W , and Wolf, M Am J of
Syphilis, Gonorrhea and Venereal Dis
30 47, 1946
6 Fhppin, H , Reinhold, J G , and Philhps,
F J Am J Med Scl 210 141, 1940
7 Greengard, R , and Wooley, J G J
Biol Chem. 132 83, 1940
8 Griffin, W C J Soc Cos Chem. 1 311,
1949
9 J Soc Cos Chem 5 1, 1954
10 Guide to the Use of Atlas Surfactants and
Sorbitol m Pharmaceutical Products, Atlas
Chemical Co , Wilmington, Delaware,
1958
11 Haines, B A, Ir, and Martin, A N
J Pharm Set 50 228,1961
12 J Pharm Sci SO 753, 1961
13 J Pharm Sci 50 756, 1961
14 Higuchi, T J Am Pharm Assoc (Sci )
48 657, 1958
15 Hospital Formulary, Hamilton, Illinois,
The Hamilton Press, 1959
16 Kraml, M , Dubuc, 1 , and Caudry, R
AnUbiotics and Chemotherapy 12 239,
1962
17 Lafferty, G , and Gross, H J Am Pharm
Assoc (Sci ) 44 in. 1955
18 Laug, P , Vos, E , and Kunze, F J
Pharmacol Exp Ther 89 52, 1947
19 Lichtm, J L, and Uchtin, A J Am.
Pharm. Assoc (PracU) 14 295, 1953
20 MacDonald, L, and Himmlick, R. J J
Am Pharm Assoc (Sci ) 37 368, 1948
21 Martin, A N Physical Pharmacy, Lea
and Febiger, Philadelphia, 1960
22. Nakashuna, J Y , and Miller, O H J
Am. Pharm. Assoc, (Pract) 16 496, 1955
23 Osborne, G E., and DeKay, H G J
Am Pharm. Assoc (PracL) 2 420, 1941
24 Polyglycol Esters, Kessler Chemical Cora
pany, Philadelphia.
25 Schwarz, T W, and Levy, G J Am.
Pharm Assoc. (Sci ) 47 442, 1958
200 liquid DoMge Forms Contoining tnsolubis Motter
26 Schwarz, T W Levy, G and kawagoe,
H II J Am, Phaxm Assoc. (Set ) 47
695, 1958
27 Sw-alTord. W , and Nobles, W L. J Am.
Pbann Assoc (Pracl ) 16 171, I95S
28 Tiilman, W J , and Kuramoto, R J Am
Pharm Assoc. (Sci ) 46 211, 1957
lypical Pharmaceutical Formulations for
Topical Application, Allas Chemical Com*
pany, Wilmington, Delaware, 1960
Vicher, £, Sn)der, R and Gathercoal
E. J J ^Vm Pharm Assoc, (Sci ) 26
1241, 1937
chapter 6
Semisolid Dosage Forms
Seymour Blaug, Ph D *
T he ter ms salve, ointment and cream mdi-
cate preparations that have m common the
prop^erty of bemg semisohds which are spread
easily on the skm \ While these terms are
sometimes used mterchangeably, they are at
other times used to represent gradations m
viscosity, the salve bemg considered most
viscous, the omtment less and the cream
least
Semisolid dosage forms mclude primarily
those preparations to be applied to cutaneous
tissue, such as ointments (salves, unguents)
cerates, creams, jellies, pastes, plasters and
poultices
A dermatologic prescnption is usually ap>
pli edlo h ighly sensitive, t^eased or denuded
areas, and the application of such a prescnp*
tion requires the patient’s cooperation There-
fore, such preparations should be easily ap-
plied and should be prepared so that the
completed product is not gramy to the touch
Omtments constitute one of the oldest
forms of dermatologic therapy Zopf** gives
3 bner history of the development of the
modem omtment It is mtercstmg to note
that m the 1960 National Prescnption Sur-
vey conducted by Abbott Laboratones, oint-
ments ranked third (behmd tablets and cap-
sules) m frequency of various sobd dosage
forms prescribed The human “preoccupa-
tiorTwith'outer self,” if not medical reasons,
caused skm and dermatologies to rank first
in number of new product marketings m 1961
(as in 1960) with 15 per cent of the total m
this classification
An ointment has been defined as a “fatty
preparaUon of such consistency as to be easily
applied^ the skin, with rubbmg” Our pres-
• Professor of Pharmacy, College of Pbarmaqr,
State Univenity of Iowa.
ent concept of an omtment is much broader
ointments are soft, semisolid preparations
mtended for application to cutaneous tissue
with Of without munction They may be en-
tirely free of oleagmous materials Because
of their physical properties they are used m
dermatologic therapy for three purposes ( 1 )
as lubneatmg agents (emollients), (2) as
vehicles m which to mcorporate drugs re-
quired to treat skm disorders, and (3) as pro-
lecuve coverings to prevent contact of the
skin surface with chemicals, aqueous solu-
tions and some organic solvents
There are sevc^ factors which inSuence
the selection of the type of preparation to be
used topically Among these factors are the
diagnosis, the effect desired, the condition
of the patient and the area or areas to be
treated The selection of base for the ex-
temporaneous preparation of an omtment is
the privilege of the physician However, it is
the responsibility of the pharmacist to pre-
pare products that are pharmaceutically cor-
rect In exercismg this responsibility the phar-
macist may generally make mmor changes
necessary for the preparation of a superior
product This may mvolve the use of small
amounts of inert matenals as levigatmg
and/or solubilixmg agents However, the
pharmacist must be certam that the levigating
or solubilizmg agent does not mteract or m-
terfere with the.active mgredieot and is not
considered to be a sensitizmg agent. For ex-
ample, some physicians may consider lano-
lio, used occasionally as a levigatmg agent or
for Its hydrophilic value, as a skm sensitizer
Blaug ct al * ^ ® have shown that many agents
used as solubilizers or as dispersmg agents
mteract with preservatives and active m^edi-
ents commonly used m semisolid dosage
forms
201
202 Semisolid Dosage Forms
It IS most important that the pharmacist
consult with the ph}siaan before changmg
the l)pc of base or the form of an active
constituent m a dermatologic prescnption
Alteration from an oleaginous base to an
emulsion base may effect the absorption and
percutaneous action of the active mgredieot
necessitating either an mcrease or decrease
in concentration of the therapeutic agent
EF FE CTS OF LOCALLY APPLIED
DRUGS
Topical medication is presenbed to pro*
duce a specific beneficial effect The pnncipal
effects of most substances applied to the skin
are indicated by their genenc names
Antipruritic agents relieve itchmg in van-
ous ways Commonly used agents and
strengths include menthol 0 25 per cent,
phenol 0 S per cent, camphor 2 per cent
and coal tar 2 to lOpercent
Kcratopinstic agents tend to increase the
thickness of the homy layer Salicylic acid
1 to 2 per cent is an example of a keratoplas*
tie agent, whereas stronger strengths of salt*
cylic acid are keratolytic.
Kerntofjtic agents remove or soften the
homy layer Commonly used agents of this
type include salicylic acid 4 to 10 per cent,
resoremol 2 to 4 per cent and sulfur 4 to 10
per cent A strong destructive agent is tn>
chloracetic acid, full strength.
Anticczcmalous agents remove oozing and
vesicular excretions by vanous actions Some
may act as protcctives, kcratolytics and anti-
pruritics The common antieczematous agents
include 2 per cent bone acid solution packs
or soaks, coal tar solution 2 to S per cent and
h}drocortisooc and denvatives 0 5 to 1 per
cent mcorporated m lotions and omtmeots
Antiparasilics destroy or inhibit Uvmg m-
festations Agents of this type include benryl
benzoate 10 to 30 per cent emulsion or lotion,
sulfur ointments, n-cthyl-o^otoootoluidine
10 per cent (Eurax Cream)* and gamma
benzene hexachlonde 1 per cent (Kwell
Ointment) t
* Gcigy Cbcmica] Corporalion, Yoaken, New
York
tRecd and Caxunck, Keedvrorth, New Jestej
/Vntiscptics destroy or inhibit bactena and
fungi Commonly used agents mclude lodme
1 to 5 per cent, lodochlorhydro^qmn 4 per
cent (Vioform Cream and Ointment) J and
antibiotics such as bacitracm 500 uiuts/Gm ,
tetracycline hydrochlonde omtment 3 per
cent (Vioform Cream and Omtment) t and
(Cbloromycetm Cream§) Antifungal agents
mclude Benzoic and Sahcylic Acid Omtment,
sulfur and ammoniated mercury m vanous
bases and undecylemc acid, zme undecylcnate
in vanous bases
Anliseborrbeics are agents that alleviate
seborrhea (excessive discharge of sebum
from the glands) by vanous actions, le,
antjprunucs Examples are ammoniated mer-
cury 2 to lOpercent, coal tor 1 to 5 percent,
ichthammol 4 to 10 per cent, resoremol and
sulfur omtmcnts, salicylic acid omtments
Emollients are agents that soften the skm
surface Mineral oil, white petrolatum, cold
creams and w/o emulsion bases are examples
of such agents However, recent investiga-
tions by Blank^ with callus tissue have re-
vealed that the water content of the stratum
corecum is probably the prune factor in de-
termmmg its softness and llexibihty In hvisg
skin, moisture is contmuously reachmg the
stratum comeum (outermost layer of the
epidermis) and bemg evaporated off the sur-
face of the skm as “insensible perspiration."**
One source of this moisture supply is the tmy
onhees of the ecenne glands (small sweat
glands openmg directly onto the skm sur-
face) The second source is through the
transepidcnnal transport of moisture but its
source is still the subject of discussion ** Re-
cently Mah^* demonstrated the existence of
a barrier membrane lymg just below the
stratum comeum which lumts the amount of
transepidcimal moisture which can reach the
outer layer of the skm, thus confinnmg earlier
studies of Blank ’ This moisture reachmg the
stratum comeum is m the mam evaporated
into the atmosphere but a small percentage
IS retained in the stratum comeum, account-
ing for Its softness and flexibihty It has been
demonstrated* ** that there is present m the
tOba PbannaceutJcal Products, loc., SummiC,
New Jersey
t Parke Davu and Co , Detroit, Micbigao.
Classification of Ointments 203
stratum comeum a water-extractable mtroge>
nous matenal capable of bmdmg up to 3
tunes Its weight in water Should there be a
deficiency of water-bmdmg matenal m the
stratum comeum, a dry s^ condiUon may
result
Excessive moisture loss can occur when
the water vapor pressure m the surrounding
atmosphere is extremely low, such as exists
under low relative hunudi^ conditions espe-
cially on cold, windy days
Blank^ and Peck** have shown that ole-
aginous matenals such as mmeral oil and
lanolm per se do not soften dead, dned and
callus tissue However, the action of these
matenals may be different on livmg skm *
Oleagmous matenals may act as skm sof-
teners by retarding moisture evaporation from
the surface of the skm by forming an occlu-
sive film which retards moisture evaporation
Matenals that absorb moisture from the air
-and add such moisture to the stratum cor-
neum or materials that retard moisture loss
from the skm by virtue of their emulstfymg
abihty may be classified as moisturizing
agents m that they aid m increasing moisture
content and hence the softness of the skm
Protectives are agents that protect the skin
agamst moisture, air and chemicals Petro-
latum, zmc oxide ointment, starch omtment
and silicone omtments and lotions fre-
quently are so employed Water-removable
emulsion bases do not protect the skm very
well agamst aqueous solutions However, sun-
screemng agents that filter out ultraviolet rays
may be mcorporated m vanous types of der-
matologic vehicles The protective agent in
this case would be the active mgredicnt, not
the base
CLASSIFICATION OF OINTMENTS
Omtments are usually classified accordmg
to their composition and/or their therapeutic
action, based on their degree of penetration
on application to the skm.
Based on composition, omtments can be
classified as follows
1 Oleaginous or Hydrocarbon Bose*
Petrolatum, fixed oils of vegetable ongin,
mixtures of petrolatum with wax or
other stiffening agents, oils of ani-
mal ongm, sui^ as lard and silicones
A Anhydrous
B Nonhydrophihc
C Insoluble m water
D Not water removable
2 Absorption Base
Hydrophilic bases such as Wool Fat and
Hydrophilic Petrolatum
A Anhydrous
B Hydrophilic
C Insoluble m water
D Not water removable
Hydrous (Emulsion Base, w/o) — Hydrous
Wool Fat (Lanolm) Rose Water
Ointment, Petrolatum Rose Water
Omtment
A Hydrous
B Hydrophilic
C Insoluble m water
D Not water removable
R Water in-oil emulsion
3 Emulsion Base (o/w)
Hydrophilic Omunent, vanishmg creams
A Hydrous
B Hydrophihc
C In^luble m water
D Water removable
£ Oil ID water emulsion
4 Water Soluble Base
Polyethylene Glycol Ointment
A Anhydrous
B Hydrophilic
C Water soluble
D Water removable
E Greaseless
Goodman** classified omtments accordmg
to their degree of penetration on apphcation
to the skm as
1 _ Epidennatic omtments. or tho se wh ich
demonstratelittle or no power of penetration
into the skm. This group includes the ole-
agmous and the hydrocarbon bases
2 Endodermatic omtments, or those which
possess some power of penetration mto the
skin. Wool fat, lard, lanolm and vegetable
oik are mcluded m this group
3 Diadeimatic omtments, or those which
penetrate the skm peimittmg or encouragmg
^teouc absorption of active constituents m-
coiporated m the base Emulsion type and
water-soluble bases belong to this cl^s
Lane and Blank** have classified omtments
and dermatologic vehicles accordmg to physi-
cal differences between the vehicles, i e ,
204 Semisolid Oojage Form$
aqueous vehicles, eg, water, aqueous lo>
tiOQS, vehicles \Hhich act as oils, c g , petro-
latum, wool fat, pastes, vehicles whi^ act
as powders, c g , starch, talc, vehicles which
act as organic solvents, c g , alcohol, ether,
acetone
GENERAL INDICATIONS FOR
OINTMENT BASES
It is not possible to list completely the
specific vehicle m which to incorporate a
particular drug for the best treatment of a
given disorder However, the pharmacist
should be able to recommend to the general
practitioner or the dermatologist the type of
base that can be used to produce a stable
antibiotic omtmcnt, or that can be used as
a slun lubricant or as a vehicle to be used on
the sqalp He should also have a general
knowledge of the factors that promote the
penetration not only of ouitments but also
of other topical preparations Generally, the
o/w emulsion bases or water soluble bases
arc mdicated when vehicles which are water
removable and not greasy to the touch are
desired As vehicles for medication to be
applied to the scalp , they are most suitable
because they can be easily washed out of the
hair They may be preferred for cosmetic
reasons
Water*in*oil emulsion bases form rela-
tively occlusive oil films on the skm surface
They arc little afTccted by atmospheric con-
ditions and exchange water vapor slowly
They are not very miscible with sweat Con-
sequently, they promote the accumulaUon of
sweat at the skm-velucle interface producing
hydration of the skin surface Hence, watcr-
in-od emulsions arc used to provide lubnea
tion and arc especially indicated when the
skin IS dry Olcagmous vehicles difTer from
water m-oil emulsions to the occlusivcncss of
the film formed on the skin surface
Olcagmous vehicles arc also indicated
when skm lubrication and h)dration are de-
sired, smcc, like water m*oil emulsions, they
form occlusive oil films on the skm surface
^Thcy differ from watcr-m-oil emulsions onlyt
|m the exaggeration of this occlusive char-\
acter
For most antibiotics, inert oleaginous or
anhydrous w/o emulsion bases offer greater
stability than o/w emulsion bases or the water
miscible, hygroscopic bases
The nonvolatile water-miscible vehicles
such as Polyethylene Glycol Omtment are
freely miscible with sweat They will not
soften dry skin, smee they do not retard the
evaporation of sweat, hence, they maintam
the least hydration at the skin vehicle mter-
facc Tills IS especially true when the relative
humidity is low However, such vehicles are
useful when water removability is desired,
such as for application to hairy regions
EFFECTS OF VEHICLES ON
THE SKIN
Hydration o! the Skm, A large percenta ge
of topical preparations are used soldy for
their physical effect on the skm surface, such
a^the control of hydration Other topical
preparations are used as vehicles, and their
primary function is to deliver an mcorpo-
rated medicament to a certain area of the
sUn Before discussing the effect of the
vehicle on drug diffusion and penetration, let
us consider the role of the vehicle or base on
the degree of hydration induced in the stra-
tum corncum
The stratum corncum or homy.laycr of
the epidermis is the outermost layer of the
skm it 15 made up of stratified layers of dead
kcraunizcd cells that arc constantly bemg
shed The chemical protein m_ these cells,
keratin, is hygroscopic and softens when it
contams sufficient water This water diffuses
from mner layers of the skm and may be
taken up from the atmosphere under certam
conditions Monash and fllank®^ and Mon-
asb^ have demonstrated that the inner two
thirds of the stratum corncum constitutes the
mam barrier to water loss, and that the outer
one half to two Uiirds of the stratum comeum
IS the mam bamer to percutaneous penetra-
tion The thickness of this outer keratm area
differs in different parts of the body accord-
mg to the degree of protection required,
bemg thickest on the palms of the hands and
the soles of the feet Hence, penetration may
proceed at a slower rate through skin areas
with a thicker layer of outer keratm, being
drastically reduced through the palms and
the soles On the other hand, the outer kcra-
tm area is exceptionally thm on the face, a
Effects of Vehicles on the Skin
205
point to be remembered m considenng the
possible penetration of cosmetic matenals
The degree of h)[^ation mduced m the
stratum come um is one of the more impor-
tant characterist ics of ji vehicle or other topi-
cal preparation As the permeability to water
vapor of the” omtment or the lotion film on
the skin increases, there is a corresponding
decrease m the degree of equihbnum hydra-
tion mduced m the stratum corneum
Oleagmous vehicles are the most occlusive
and mduce the greatest hydration of the
stratum comeum through sweat accumula-
tion Oleagmous vehicles containmg a lipo-
philic surfactant, such as anhydrous water-
in-oil emulsion vehicles, are somewhat less
occlusive
Oil m water emulsions probably show the
greatest variation m permeability to water
vapor This is due to the greater variety of
mgredients m such formulations Shelmire*'
has shown that a basic formula (oil sur
factant and water) for an oU-m water emul-
sion vehicle will not produce a film of maxi-
mum water retaining capacity unless a fourth
substance is added, usually one of the long*
chain saturated alcohols, esters or acids As
the outer phase of an oil in water emulsion
evaporates from the skin the emulsion tends
to invert, leaving a continuous oil film con
tammg other dissolved or suspended sub-
stances The long chain alcohols esters and
acids dissolved or suspended m the oil prob-
ably increase the viscosity and the cohesion
of the oil film, thus inhibiting the evaporation
of water from the skin surface
Powers and Fox*^ studied the effect of
representative fatty matenals, humcctanls
and emulsifiers on rate of moisture loss from
the skm The matenals which retarded mois-
ture loss from the skin most effectively were
primarily the nater-msoluble non surface-
active fatly or oily compounds This type of
compound forms a scmiocclusive bamcr on
the surface of the skin, thus retarding the
rate of water evaporation
Surfactants used in oil m water emulsions
had little effect m influencing the rate of
moisture loss from the skm
Glycerme and prop>Iene gl)Col, used m
many emulsion formulations, consistently in-
creased the amount of moisture lost to a dry
atmosphere Although these humcctanls will
/
decrease the rate of water loss from the
vehicle itself and prevent crust fonnalion,
they will actually mcrease the rate of water
loss from the stratum comeum Certam of
the water-soluble polyoxyethylene esters and
ethers also did this Humectants and poly-
oxyethylene esters and ethers may accelerate
water loss by drawing moisture from withm
the skm to the surface under dry or low hu-
midity conditions They may also mterfere
with the ngidiQ' of the final oil film on the
skin and probably interfere with mversion of
an oil m water emulsion
Water-soluble vehicles such as Polyethyl-
ene Glycol Ointment do not wet the skm and
do not retard the evaporation of water from
the stratum comeum, hence, they produce
the least change m hydration from the time
of application until equilibrium
In summary, water containing vehicles wet
the sbn mitiaily, but the degree of hydra-
tion decreases as the aqueous phase evapo-
rates Although oleagmous vehicles do not
wet the skm mitially, they do produce a
steady mcrease m hydration as moisture is
prevented from evaporating by the occlusive
oil film
General Factors Affecting
Percutaneous Absorption
The most important route of absorption
through the skm is through the appendages,
1 e , the sebaceous and the sweat glands The
openmgs of the skm glands offer a ready pas-
sage for medicaments to the cells Unmg the
walls of the glands Penetration through the
walls into the surrounding epidermis and,
thence, to the general circulation eventually
occurs Smee the pores of the glands are
filled with hpoid material and air, it is diifi-
cuU for water soluble matenals to penetrate
unless the vehicle contains substances which
permit the medicament to mix with the con-
tents of the glands However, Rothman*® ex-
plained some aspects of percutaneous absorp-
tion by assuming the existence of a ‘ bamer ’
thought to be located m the outer stratum
comeum The ‘barrier” itself behaves like a
scimpermeablc membrane, exhibiting strong
negative absorption toward some matenals
Hydration of this ‘ bamcr” membrane ap-
pears to mcrease the rate of passage of dl
matenals which penetrate the skm, probably
GLYCOL SALICYLATE METHYL SALICYLATE ETHYL SALICYLATE
206 Semiselid Dotago Forms
Fio 76 A Unnary
excrctJOQ data showing
the iniluencc of niois*
ture oa the pcrcutan&>
ous absorptiOQ rale of
ethyl salicylate • Hy>
drous system, O Anhy-
drous system
Fio 76 B Unnaiy
excretion data showing
the lotiucoce of mois-
ture OS the percutane-
ous absorption rate of
methyl salicylate • Hy-
drous system, O Anhy-
drous system
Fio 76 C. Unnary
excretion data showing
the influence of mois-
ture on the percutane-
ous absorption rate of
glycol salicylate, • Hy-
drous system, O Anhy-
drous system.
Effects of Vehicles on the Skin
207
Table 31. ExPERiitENTAL Excretion Eates and Other Physical Cosstants
OF THE Test Penetrants*
No
Glycol
Saucylate
Methyl
Saucylate
Ethyl
Saucyiatb
1 Hydrous system rate (moles/100 cmVhr )
11 7
86
23
calculated as the salicylate ester
2 . Anhydrous system rate (moIes/100 cmVbr )
13
27
15
calculated as the sahcylate ester
3 Rate hydrous system
90
32
2.0
Rate anhydrous system
4 Per cent water solubUity
127
0 08
0 03
5 Distribution coefficient (olive oil/water)
77
343
1,170
6 Relative distribution coefficient (glycol salt
1
45
152
cylate 1)
• From I Pharm. Set 50 29 1
by increasing the size of the holes in the matic difference m absorption rates After
membrane Generally, medicaments soluble approximately 6 hours the excretion rate of
m oil and water are most strongly absorbed salicylate is at a steady state
on the ‘bamer” membrane and appear W AsshowninTabIe3I,lheabsorptioarates
require the least hydration of the membrane for the three drugs can be related to their
for percutaneous absorption Drugs soluble dislnbuuon coefBcients and their per cent
m water only require a greater degree of hy-
dration, and water-insoluble drugs appear to
require the greatest hydration of the stratum
comeum m order to penetrate ^
Usmg an absorption cell attached to the
forearm of human subjects, Wurster and
Kramer^’ studied the absorption of three u
liquid salicylate compounds under hydrous
and anhydrous skm conditions Salicylates ^ _
studied were ethyl sahcylate which is the
least water soluble, methyl salicylate of me- —
dmm solubility, and glycol sahcylate which < ^
IS the most water soluble Unnary saheylaie <o {2
was deter min ed at various lime intervals and _j ^
plotted against time Figures 76 A, 76 B and o S
76 C show graphically that the absorption >-
was greater when a hydrous skm condition ^
was mamtamed The more water-soluble
drug, glycol sahcylate, was aided to a greater
degree by the presence of moisture than Vicre
the less soluble compounds
Ihese figures also show that the curves
plateau or the rate of excretion becomes a
constant At this pomt the excretion rate of
the sahcylate is the same as the absorption ~ a . .
•' ^ Fio 76 D Accumulative unnary sah-
. , cylatc data showing influence of moisture
An accu mul ative plot of the glycol sail- on percutaneous absorption rate of glycol
cylate absorpuon under hydrous and anhy- sahcylate. • Hydrous system O Anhy-
drous conditions (Fig 76 D) shows the dia- drous system.
HOURS
208
Semisolid Dosage Forms
solubility m water As the dutnbutioit co-
cflicicnt decreased, the absorptioa rate in-
creased under h}drous conditions The rates
shown in Nos 1 and 2 are for 100 cm’ of
skin surface Wurster and Kramer*’ demon-
strated that the excretion rate is directly
proportional to the area of skin surface
through which the salicylate diffuses No 3
expresses the ratio of the rate m the hydrous
system to the rate m the anhydrous system
The ratio shows the increase in rate pro-
duced by skm hydration This ratio decreases
with the decreasing water solubility of the
salicylate
Other factors that must be coasidcccd m.
any discussion of drug diffusion and percu-
taneous absorption are
Area to Which the Vclilclc Is Applied.
There can be little doubt that drugs which
penetrate the stratum corncum do so most
readily where the outer kcratic layer is thin
Penetration proceeds slowly through skin
areas with a thick layer of outer kcratm, such
as through the palms and the soles The
sebaceous and the sweat glands per unit area
would also be a factor, although MacKce
et aP* found that sweat pores were not nec-
essary for penetration, since no evidence was
produced of penetration of vehicles applied
to the skin of the palms of infants, which
contains numerous pores and well developed
ss\cat glands but no follicles They con-
cluded that absorption takes phcc into the
homy layer and the follicular opemngs of
the epidermis
Solubility Characteristics of the Drug in
the Vehicle. Using the ontiwhealing effect
as a criterion for absorption of pynbcnzaminc
hydrochlonde from various vehicles. Peck
et al ” found that the best results were ob-
tained with an oil-in water emulsion base
Since pyribcnzamme hydrochloride is water
soluble. It IS easier for an o/w emulsion base
to deliver a water-soluble medicament to the
skin Michclfcldcr and Peck’’ also shoued
that pynbcnzaminc hydrochlonde penetrates
best through the normal skin from a water-
miscible emulsion base They also showed
that pynbenzamme base is absorbed best
from a fatty base However, pynbcnzaminc
base is absorbed better than die hydrochlo-
nde, even from an o/vv emulsion base Ap-
itly, hpoid solubility of the active m-
grcdient is more important than the vehicle
Itself
Shclmirc** demonstrated that diffusion to
the skm surface of a highly oil soluble drug
was greatest from a petrolatum vehicle Ap-
parently, polyethylene glycol vehicles can
provide a relatively high surface concentra-
tion of watcr-msoluble drugs with little per-
cutaneous absorption A drug highly soluble
m oil and water did not penetrate when in-
corporated m a polyethylene glycol vehicle
Mrcbelfelder and Peck’’ also found that a
polyethylene glycol base is not a suitable
vehicle for pyribcnzamme hydrochlonde, so
fac as penettaUon » conxmeoed The rela-
tively high surface concentration of water-
msolublc drugs produced by polyethylene
glycol vehicles is probably due to the fact
that polyethylene glycol vehicles accumulate
the least sweat at the skin vehicle mterface
and, thus, present less of an aqueous barner
to the diffusion of water insoluble drugs from
vehicle to sbn surface Since polvetbyleoe
glycol vehicles do not maintain hydration of
the skin surface, it is understandable why
water-soluble medicaments arc not trans-
ferred readily to the skm surface
Covcruig or Bandaging Over the Vehicle.
This factor is most important when usmg
water miscible vehicles, since the occlusion
or covering of such vehicles will increase the
solution of water soluble drugs by lohibiung
the evaporation of sweat or the aqueous
phase The quantity of drug dehvered to the
skm surface should increase, and penetration
may also increase due to an increase m hy-
dration of the stratum corncum
Amount of Inunction. MacXee and his
co-workers’* and Peck et a/” showed that,
in general, the longer the period of inunction
the greater is the amount of drug absorbed.
The viscosity of the vehicle is related to the
period of inunction, since it is easier to
force a base of low viscosity into the gland
openings
Concentration of Medicament ui the
Vehicle. The rale of penetration of a me-
dicament appears to increase m direct pro-
portion to the concentration in the vehicle,
provided that the solubility limit of the me-
dicament IS not exceeded The action of a
medicament on the skm may not increase m
direct proportion to its concentration when
Oleaginous Bases 209
the medicament is insoluble or only slightly
soluble m the vehicle “ **
Frequency of Reapplication and Length
of Contact Tune of Vehicle on the Skin. In
general, the quantity of drug absorbed is pro-
portional to the time the vehicle is in con-
tact with the skm However, this may be
affected by secondary changes of drug con-
centration due to changes in de^ee of skm
hydration and evaporation of water from an
emulsion vehicle Malkinson"^ demonstrated
that rate of penetration of a medicament de-
creases with time as the tissues become satu-
rated with the drug
Condition of the Skm Probably the most
important single factor in determining rate
of drug penetration is the condition of the
outer stratum comeum Several mvestiga-
tors“ ** demonstrated the effect of epider-
mal damage m percutaneous absorption
When the stratum comeum is not mtact, it
is apparent that differences between vehicles
with regard to rate of drug penetration will
be minor Medicament concentration be
comes mcreasiogly important when the vehi-
cle IS applied to injured or diseased skm
This is understandable because differences to
hydration induced m the stratum comeum by
various vehicles become of less importance,
leaving other factors such as solubility and
concentration of medicament as factors to
consider m percutaneous absoqjtion The
vehicle assumes more importance when the
stratum comeum is mtact
OLEAGINOUS BASES
Oleagmous bases mclude lard, vegetable
oils (usually used as components of vehicles)
and hydrocarbons such as petrolatum, liquid
petrolatum, paraffin and jelled mineral oil
Also included m this group of scraisolid
preparations arc'Bases consisting of or con-
tammg silicones, used primarily as protec-
tives
Lard. The purified mtemal fat of the
abdomen of the hog was employed exten-
sively m the past as a vehicle or as a com-
ponent of vehicles It is soft and greasy and,
like other vehicles in this category, it forms
an occlusive film when applied topically
Lard will absorb approximately 15 per cent
of Its weight of water Sufferung agents such
a s spermaceti or, b eeswa x ^_be mcor-
ported to improve its physical properties
Lard has largely been replaced by benzo-
mated lard prepared by the addition of 1 per
cent Siam benzoin Thij_preparatign _has
better keepmg qualities than lard because of
the balsamic acids (primarily benzol^c acid)
and coDiferyl benzoate contained m the Siam
benzom These constituents serve as anti-
oxidants and preservatives Lard belon gs to
the endodermatic class of oi ntments, smee
absorption of m edicaments from lard bases
has been demonstrated "
Vegetable Oils. Olive, cottonseed persic,
sesame and other oils are seldom employed
as vehicles However, they are frequently
employed m sermsolid preparations as soften-
ing agents for preparations containing waxes
or for their emollient effect They are often
employed m emulsion lotions and emulsion
type omtment bases
Petrolatum (Petroleum Jelly). Petrolatum
N F li a tasteless, odorless, unctuous, mass
obtained from petroleum It vanes m co lor
from yellow to light amber White Petrolatum
USP is petrolatum wholly or nearly de-
colorized It IS preferred when a white .o.r a
translucent ointment is desired Both petro-
latums consist of microciystalhne, sobd hy-
drocarbons suspended in liquid and semi-
solidjiydrocarbons
Petrolatums are employed extensively as
components of many emulsion bases, either
oil m-water or water in-oil types T hey are
also u sed a5_occlusivc^ emollient, protective
covenngs for the Steigleder and Raab<*
studied a vanety of seinisolid bases with re-
spect to their protective action on the skin
surface against contact with water White
petrol atum showed the best_protective action
Addition onnicone dfd not enhance the
protective qualities of the base Data indi-
cated that ointments have a prolonged influ-
ence on the skm surface, even when pro-
tection against water was no longer complete
Petrolatu m bases a re ffeasy and difficult
to remove from^the skin ^so, they_are m-
capable of absorbing, aqueous solutions (5
to 10^ of water can be mcorporated by
trituration) However,.this ^ be remedied
by mcorporating 15 per cent of wool fat
with petrolatum, this imxture will absorb up
to SO per cent of water
210 Semisolid Dosage Forms
The major advantage of hj drocarbon oint-
mcDts over oleaginous bases prepared from
animal fats and vegetable oils is that they do
not raaadify Petrolatum Rose Water Oint-
ment L/SP possesses this advantage over
the Rose Water Omtmcnt prepared from a
vegetable oil
1 5
Iodine 03
Petrolatum q4 30 0
Sig Apply at bedtime
Dissolve the iodine m a small amount of
water containing 0 3 Cm of potassium iodide.
Incorporate the solution m 10 Cm of wool fat
and then incorporate the petrolatum
2 n
Starch
200
Zme oxide
too
Petrolatum q s
600
Stg ProtecUve oiotmenL
Apply as di-
reeled
Incorporate the starch and the zinc oude by
levigating With the petrolatum A portion of
Uie petrolatum can be toeltcd and used as the
levi^Ung agent. Incorporate the remaitung
petrolatum
n
Peru balsam
50
Sulfur
50
Salicylic acid
30
Petrolatum qji
300
Sig Apply locally as directed
Levigate the sulfur and the salicylic acid with
a small portion of the petrolatum. Mix the Peru
balsam with an equal weight of castor oil and
incorporate with the concentrate, then add the
remainder of the base and mix well
Prescription 1 demonstrates the incorpora-
tion of a water soluble medicament m pet-
robtum. Medicaments such as iodine, mcr-
bromm, etc , should not be meorporated by
tnturation 'They must be dissolved in water
prior to mcorporation in the base Presenp-
tiOQ 2 is a stiff, protective type of omtmcnt.
If a levigating agent such as hquid petrolatum
IS used, the preparation becomes too soft In
general, the vehicle itself should be used os
the levigating agent in most omtment pre-
senpuons Ihc use of auxiliary agents such
as liquid petrolatum results in undue soften-
ing of the preparation Prcscnption 3 illus-
' 'cs the use of a spcaal levigating agent.
castor oil It is used to prevent the * bleeding”
or separation of Peru balsam from the
oleagmous vehicle smee Peru balsam is only
slightly soluble in most oleagmous vehicles
Ichtbmnmol also con be readdy incorporated
m petrolatum by first triturating it with an
equal weight of castor oil Icbthammol Omt-
ment N F employs wool fat as the levigating
agent However, Peru balsam and ichlham-
mol can be incorporated directly m emulsion
bases such as Hydrophihc Ointment USP.
to produce a stable pr^uct
Anh ydrous pe trolatum bas es are also em-
ployed exte nsivfly _when. antibiotics sudi as
penicinSr the tetracyclines, chloramphemcol
and bacitracm are to be prepared m a senu-
soUd dosage _form Extensive hydrolysis
occurs if these antibiotics are incorporated
in water-containing emulsion bases or m
water soluble bases such as Polyethylene
Glycol Omtment U SP If it is desired to m-
corporate these antibiotics m emulsion type
or water soluble bases, the ointments should
be refrigerated. Neomycin, tyrothryem and
polymyxm B are stable at room temperature
IQ ^ t^s of ointment bases
>Vlulc Ointment, US P and Yellow Oint<
meat,NF These h ydroc arb on bases cons ut.
rcspci^vely, o_fwhitc and yellow petrolatum,
stmehed (respectively) with wbite a nd yellow
Both serve as emollient jrehicles for
other ointments Yellow Omt men t is also em-
pioyed as the vehicle m Chrysarabin Oint-
meot Both the White and the Yellow Omt-
meats are known as Simple Ointment \Vhite
OmlmCDt should be employed to_ prepare
white omtmcnis and Ycllowpmtmcot should
be used to prepare colored ointments when
Simple Omtmcnt is presenbed Variations
are permitted m ^e amounts of petrolatum
and wax, to mamtam a suitable consistency
at extreme climatic conditions
n
Dismuth subnitrate
300
White wax
100
White petrolatum
600
Sig Apply as directed
Melt the wax and the petrolatum on a water
bath Use a portion of the melted base to levi
gale the bismuth suboitrate Stir the remaining
base until congealed and mcoiporate the well
tnturated bismuth suboitrate. A veiy sliil prep*
anitjon results
Oleaginous Bases 21 1
5 5
Zinc sulfate
Sulfurated potash
Calamme aa 4 0
Wool fat
Petrolatum qs 600
Sig Apply to skm
Prepare white lotion Filter off the water and
incorporate the residue m the wool fat. Levi
gate ^e calamine on a slab with a small amount
of petrolatum Incorporate the calamme and
the white lotion residue in the remamtog
petrolatum
lodme
10
Potassium iodide
10
Yellow omtment q s
30 0
Sig Apply as directed
Dissolve the potassium iodide in a small
quantity of water Dissolve the iodine in this
solution Incorporate the iodine solution in 5
Gm. of wool fat and incorporate sufficient
yellow ointment to make 30 Gm
Plasttbase* (Jelene) con sists la fgelv__fif
mineral oils jejied with high molecular weight
hydrocarSoowMes The liquid phase is
mobilelmd is'ief^ed m what is believed to
be a matrix of submicroscopic interstices
An unique feat ure of P lastit^e_^ its u n-
usual jemperature- visco sitv relauonsbip It
melts at 90 to 91®*C and mamtams its omi-
mentlike consistenqi over a wide tempera-
ture range ( — 15® to 60®)
la-vitro studies^* mdicate that Plasti-
base permits a greater release of an incor-
porated medicament than does petrolatum.
This IS associat ed with t he mobility of_th e
Oil phase, penm^g^ a dr ug to d iffuse into
the suiroimdmg media
Menthol, salicylates and camphor are dis-
solved by_PIastibase, producing omtments
that are too soft This is probably due to
mteractio^iwth the high molecular weight
waxes used to gel the mineral oil Cod tar,
when incorporated m Plasubase, also pro-
duces a very soft ointment PrescnpUons
using Plasubase as the vehicle cannot be
prepared by fusion because it is difficult to
cool the resulting mixture to a smooth con-
sistency In preparing PlasUTiase com-
mercially, a shock cooling procedure (\ery
• Trade name of E. R- Squibb & Sons, Div of
Olm Mathicson Chemical Corp , New York. N Y
rapid coolmg to a low temperature) is used
Silicones c annot be considered as hy dro-
carbon matenali^ since th eir _basic\structure
IS not c arbo^but an alterna te chain of silicon
and oxyg en ato ms, i e , -:gi rO-S i-0 They
are included m the oleagmous group ofomt-
ments because thjy me oily fluids or greasy
semiso lids similar m appearance to_aiid
possessmg so^e of the physical properties of
liquid petrolatum and petrolatum such as m-
ertness antTimmiscibility \y^"water
Physically, silicones vaiy from low vis-
cosity fluids through high viscosity hquids
and semisolids to solids, dependmg on the
substituent orgamc groups attached to the
sihcon and the degree of cross-Imking of the
polymer
Sili cone fluid s are u sed extensively m semi-
sohd preparauons to provide a protective
bamer "against common skm irritants The
fluids arc odorless, tasteless^-relauvely mert
chemically and physiologically®® and water
repellent
Dunethicone, a water-repellent silicone
fluid consisting of dunethylsiloxane polymers,
IS used m the form of an omtment contam-
mg 30 per cent silicone m a petrolatum base
Dunethylsiloxane polymers are commercially
available as D C 200 (Dow Commg) fluids
of vanous viscosiUes Usually, the 1,000-cts
fluid IS used m protective omtments
CH,
CHj— i-o-
CH.
CHj
sl-o
I
CH,
Dunethicone
— Si-CHa
cL
In addition to the mcoiporatmg of silicone
fluids m petrolatum, these can be emulsified
in oil m water or water m-oil type of emul-
sions, m much the same maimer as mmcral
oil Plem and Plein®* have prepared sihcone-
contammg omtments such as silicone cold
cream, silicone hydrophihc omtment, etc
Vaoistl Silicone Omtment®*
7 B
Steanc acid (Fearlsteanc)
100
Synthetic Japan Wax
2.0
DC 200, 1000 CIS Silicone Fluid 200
Potassium hydroxide
05
Mcth}Iparabeo
0025
212 Semitolid Dosage Forms
Propylparaben 0015
Distilled water 67 S
Worm the aqueous mixture of the potassium
hydroxide and the parabcos to 75° and slowly
add It to the warmed stearic acid Japan Wax,
D C 200 mixture. Sur until the ointment
congeals
Steiglcdcr and Raab‘^ studied the protec-
tive action of a petrolatum ointment contain-
ing 25 per cent silicone and a neutral, pet-
rolatum free omtmcnt contammg 2S per cent
silicone These were compared with the pro-
tective action afforded the skin sut^cc
against contact with water by petrolatum.
Hydrophilic Petrolatum USP , Hydrophilic
Ointment US P , Zinc Ointment USP and
Olive Oil USP White petrolatum showed
the best protective effect
Spccialties Containing Silicones
AND Silicates
Covtconc (Abbott) — a plasticized combma
tion of dimeihylpolysiloxane, miroccUutose and
castor oil in a vanishing cream base, used to
protect the skin from occupaiionol dermatoses
and skin contact allergies
Domiconc (Dome) — Acid Mantle Cream (a
buffered solution of aluminum acetate m an
oil m water type of emulsion base) contaiiung
20 per cent silicone
Pro-Dcma (Westwood)— a nongreasy cream
containing 52 5 per cent silicone
Silicotc (Anur-Slonc) — a specially refined
petrolatum base containing 30 per cent silicone
Kcrodex Bamer Creams (Ayerst) — available
as water repellent and water soluble prepara
Uo!u containing magnesium silicate, liiatomacc-
ous silica, zinc oxide, zinc stearate and kaolin
- ABSORPTION BASES
The term absorption as used m the above
title docs not refer to the therapeutic cfDcacy
of bases when applied to the skin but to their
hydrophilic or water-absorbing properties
’^is dass of bases may be divided into two
groups, one group consisting of anhydrous
bases which permit the incorporation of
aqueous solutions with the formation of a
water m*oil emulsion, i c , Hydrophilic Pet-
rolatum US P , Wool Fat USP The second
group consists of hydrous watcr-m-oil emul-
sions, which permit the mcorporation of ad-
ditional quantities of aqueous solutions, i e ,
Hydrous Wool Fat US P , Rose Water
Ointment N F and Petrolatum Rose Water
Ointment US P
Hydrophilic Petrolatum USP This ba se
enables the pharmacist to incorporate water
or a solution of medicmal substances m
water rcsulling m the formation of a water-
in-oil emulsion The original formula for
hydrophilic petrolatum contained cholesterol
wool fat \Vqpl fa^has since been deleted
and the cholesterol content increased from 1
to 3 per cent, enabhng the incorporation of
large quantities of aqueous solutions
8 I)
Aluminum acetate solution 100
Hydrophilic petrolatum q s 1000
Sig Apply as directed
University of Iowa Absorption Base
9 »
Cholesierol 300
C^tlonsced oil 300
White petrolatum 940 0
Heat the while petrolatum and the cottonseed
oil to 145° C Remove from the beat, add the
cholesterol and siir uniil congealed
Anhydrous Lanohn USP (Wool Fat),
Wool fat IS the purified, anhydrous, fatlike
substance from the woolof sheep It contains
the sterols cholesterol and oxyctiolestcrol as
well as tntcrpcnc and aliphatic alcohols Al-
though called a fat, wool fat is more accu-
rately classified chcmirally_as a wa x The
crauisifymg and the emollient actions'’of
lanolin arc thought to be due to the alcohols
which arc found m the unsaponifiablc frac-
tion when lanolm is treated with alkali Wool
wax alcohols constitute about SO per cent of
this fraction which consists of approximately
30 per cent of cholesterol, 25 per cent of
lanosterol, 3 per cent of cholcstanol, 2 per
cent of agnostcrol and 40 per cent of various
other alcohols Wool fat is capable of taking
up about twice its weight of water It is too
sticky and tenacious to be used by itself but
mixes readily with other oleaginous matcnals
to increase the hydrophilic property of the
base. Lanolm USP contains 25 to 30 per
cent of water
10 »
Bufow s solution 5 0
Zinc oxide 3 0
Absorption Boses 213
Table 32 Water Number of Fatty Alcohol, Wool Fat and Petrolatum Mixture
Water Number
Fatty Alcohol
Wool Fat
Petrolatum
White
Petrolatum
Yellow
PETROLATUXt
Cetyl alcohol, A%
10%
86%
1041
108 3
Stearyl alcohol, 6%
10%
84%
1182
1145
Boric acid ointment
10 0
Lanolin
50
White petrolatum q s
60 0
The Bntish Pharmacopeia contains a
monograph for an absorption base under the
name Wool Alcohols Ointment
Wool Alcohols Ointment B P
11 n
Wool alcohols 60 0
Hard paraffin 240 0
White or yellow soft paraffin KK) 0
Liquid par affin 600
Melt together and stir until congealed
Wool Alcohols IS a crude mixture of sterol
and tnterpene alcohols prepared by hydro-
Irang wool fat with alkali and separatmg the
fraction containing cholesterol and other
alcohols The preparation is clauned to be
much less odoriferous than wool fat
Rose Water Ointment N F (Cold Cream).
This preparation was ong^inated by Galea
and waI”knovm for centuries as Ceratum
Refngerans Cold cream prepared with ex-
pressed almond or persic oil is readily ab-
sorbed by the skm and produces a sensation
of coolness The emulsifier m cold cream is
the sodium salt of the acids found in sper-
maceti and white wax Ctoj.d cream is used as
an emollient ointment or as a vehicle for
medicaments It belongs to the group 2 type
of absorption bases, the hydrous water-m-oil
emulsions
Petrolatum Rose Water Ointment US P
This preparation differs from Rose Water
Ointment NF m the replacement of the ex-
pressed almond or persic oil by an equal
weight of liquid petrolatum This produces
an ointment which is not subject to rancidity
However, petrolatum rose water omlmcnt
IS nonabsorbent and remams greasy to the
touch, produemg less coolmg sensation than
cold cream The pclrolatum-contaming oint-
ment IS used primarily as an emollient and a
cleansmg cream”(uscd to remove makeup
and grease pamts) It is very similar to the
commercially available cleansing cream or
theatneal cream
Water Number
Most oleagmous bases such as lard and
petrolatum can become absorption bases by
the addition of an ingredient or ingredients
that mcrease ihe water number of the
oleaginous base Caspans and Me) defined
the water number as the largest amount of
water (in Gm ) that 100 Cm of an oint-
ment base or fat will bold at normal temper-
ature (20*) They also described a titration
method for determining the water number
of an ointment base A more sensitive method
utilizes the Karl Fisher reagent and an instru-
ment such as the aquameter Halpem and
Zopf*’’ mvestigated the hydrophilic properties
of the saturated fatty alcohols from Cio to
Ci$ Casparis and Meyer reported the water
number of petrolatum as 9 3 to 15 6 and lard
as 7 5 They found that 4 per cent cetyl
alcohol increased the water number of pet-
rolatum to between 38 8 and 51 5, while 3
per cent cetyl alcohol mcreased the water
number of lard to 244 9 There appears to be
a definite relationship between concentration
of fatty alcohol and the water number of the
vehicle Stearyl alcohol was found to produce
the greatest potentiation of the water number
of petrolatum, although cetyl alcohol bad the
lowest optimum concentration, i e , m white
petrolatum 5 per cent cctyl alcohol raised the
water number to 38, whereas 7 per cent
stearyl alcohol raised it to 42
As shown in Table 32, combmations of
cctyl or stearyl alcohol and wool fat increased
the water number of petrolatum more than
either cetyl or stearyl alcohol alone
Smcc the water number mdicates the mau-
214 Semisolid Dosoge Forms
mum amount of water that the base will hold.
It IS advisable to add w'atcr m quantities of
10 to 15 per cent less than is indicated by
the water number Tins will preclude the
possibility of water bleeding from the base
because of temperature variations
12 K
White wax 7 0
Sodium borate 0 S
Precipitated sulfur 5 0
Rosewater 18 0
Liquid petrolatum q s 60 0
Sig Apply to skin twice daily
Melt the wax on a water bath with the liquid
petrolatum Dissolve the sodium borate in the
rose water warm to about 65^ and gradually
add the warm solution to the melted mixture
Stir until congealed Use a portion of the base
to levigate the sulfur incorporate the remain
ing base
Specialty Absorption Bases (Anhydrous
AND Hydrous)
Almatone (AImay)->a h>poaUcrgeoiC oiot
ment containing lanolin derivatives with sper
maccii and petrolatum
Aquaphor (Duke) — absorption base coo
taming 6 parts of woolwax alcohols and 94
ports of aliphatic hydrocarbons
Hydrosorb (Abbott) — a mixture of otcic acid
ester and amide of diethanolamine, oIcic acid
and petrolatum
Hydrolcx (Texas Pharmacol) — a neutral,
oleaginous absorption base consisting of sorbi
tan sesquioleate white wax and blended
petrolatums
Lanolor (Squibb)— hydrous wool fat, pan
Tied and deodorized
Nivca Cream (Duke) — an emulsion of ncu
tml aliphatic hydrocarbons in water with wool
wax alcohols
Polysorb (Fougcra) — a wax petrolatum mix*
lure containing sorbitan sesquioleate as Use
emulsifying agent
Plastibasc Hydrophilic (Squibb) — a hydro-
philic counterpart of PJasljb^c conlaiiungSS 16
per cent liquid petrolatum, 5 64 per cent poly
ethylene wax 6 per cent emulsifying agent and
0 2 per cent anuoxidant and preservative
EMULSION BASES
The outstanding characteristic of this group
of semisolid bases is w atcr removability Since
these bases arc oil m water emulsions, they
arc diluted readily by th e e xternal phase
and, hc^cc, are readily removed from“’the
skin or clothing Alihough~these bases arc
al^tcrmcd hydrophilic' bases (Hydrophilic
Ointment US P ) the y will not t ake up more
than 30 to 50 per'cent of their weight yn
water without losing their ointment con-
sistency
Emulsion bases are not a s occ lusive as
oleagmous bases or anhydrous and Hydrous
absorption bases However^ they are cos-
metically appealing and arc useful when a
medicament is to be applied to a haiiy region
such as the scalp Many cosmetic prepara-
tions such as vanishing creams, foundation
creamr, etc , arc o/w emulsion preparations
They do not leave a greasy residue when ap-
plied to the face
In addition to oil and water, an emulsion
base may coniam high molecular weight fatty
alcohols such as cetyl and/or stearyl alcohol
These alcohols improve the stability of the
base by increasing its consistency and also
enhance the water holding ability of the base
Most emuhio^baics, becausc_ot. their ex-
ternal aq^ous phase, also contain a humec-
lant such as glycenn, propylene glycol or
sorbitol These substances reduce water loss
through evaporation and may assist m ob-
taining a more intimate dispersion of oils,
grease, etc, m water
The choice of emulsifier is important, smcc
solubility of the emulsifying agent is a de-
termining factor in the type of emulsion pro-
duced In general, an agent that is soluble in
water or more readily wetted by water than
by oil will fonn an o/w emulsion Such agents
include monovalent soaps, amine soaps, sul-
fated fatty alcohols, polyglycol esters, qua-
ternary ammoruum compounds and many
nonionic polyoxyethylene derivatives Ionic
agents such as soaps, sulfatcd fatty alcohols
and quaternary compounds arc sensitive to
the presence of other ions and to changes
m pH Thus, amonic emulsifying agents such
as soaps may be mcllcctivc m formulations
contaimng buffer salts or cationic matcnals,
and cationic agents such as the quaternary
compounds arc meffectwe in the presence of
anionic materials such as soap Ointments
prepared with anionic agents arc not stable
at pH s much below 5 to 6 On the other
Emulsion Bases
215
hand, nonionic agents do not ionize, hence
are compatible with electrolytes and lomc
emulsifying agents In general, noniomc
agents are less imtating than aniomc agents,
which are less imtatmg than cationic agents
Noniomc emulsifying agents are widely
used m cosmetic and dermatologic formula-
tions One must keep m mind that preserva-
tives and medicaments may interact with the
noniomc emulsifymg agent m such formula-
tions Blaug er <3/ * ^ ® have shown that many
commonly used nomonic surfactants interact
with preservatives and active mgredients used
in semisolid dosage forms For example. Hy-
drophilic Omtraent U SP XV contained
polyoxyl 40 stearate (Myi] 52),* a non-
ionic surfactant, as the emulsifying agent
However, it was noted that medicaments
containing an acidic hydrogen such as benzoic
and salicylic acids, phenol, etc , produced a
marked softening of the base For this reason
the U^P XIV formula contairung sodium
lautyl sulfate, an anionic agent, was re-
adopted mt/SP XVI
13 n
Bacitracin 500 uniCs/Gm
Stcaryl alcohol 15 0
White wax 1 0
Gl}cenn 5 0
Myn 52 50
Water 74 0
Sig ^pply to infected area (hre* times
daily •-
Prepared as above, the preparation becomes
very soft due to interaction between the Myrj 52
and constituents in Bacitracin Replace the 5fyt]
with 2 0 Gm of sodium lauiyl sulfate Nfelt the
stearyl alcohol and the w‘%x on a water bath
and heat to about 65° Dissolve the sodium
lauiyl sulfate and the propylene glycol in the
water and heat to about 65° Slowly add the oil
phase to the water phase with stimng Stir until
the preparation congeals Levigate the baci
tracm with a small amount of the base, then
incorporate the remaining base Preparation
must be refrigerated For greatest stability baci
tracm should be incorporated in an anl^drous
base
14 n
Salicylic acid 0 6
L.CD 3 0
* Atlas Chemical Industnes, Inc , Wihmagtoa,
Delaware
Zinc oxide
30
Starch
30
Water removable base q s
300
Sig Apply as directed
Dissolve the salicylic acid in the L.C D and
incorporate in hydrophilic ointment Levigate
the zinc oxide and the starch with a portion of
the hydrophilic ointment Incorporate in the
remaining base
15 n
Salicylic ac.d
06
Sulfur
06
Neobase q s
Sig Apply to scalp
300
D
Coal tar
20
Zinc oxide
50
Polysorbate 80
05
Petrolatum q s
60 0
Sig Apply to arm daily
Mix the coal tar with the polysorbate 80
Levigate the zinc oxide with a small portion of
peirolatum and incorporate the coal tar and
the zinc oxide m the remaining petrolatum The
polysorbate 80 serves a dual purpose It func-
tions as a dispersing agent and also aids m the
removal of the ointment from the skin
17 n
Salicylic acid
06
Undecylenic acid
1 0
Hydrophilic base qs
60 0
Sig Apply between toes once daily
n
Ammoniated mercury
22%
Liquid pefro/afam
20^0
Steanc acid
8%
Cetyl alcohol
2%
Tncthanolamine
\%
Distilled water q s
Sig Apply locally p r n
60 0
The emulsifier, triethanolamine stearate, is
prepared m situ Melt the cetyl alcohol and the
steanc acid on a water bath. Add the liquid
petrolatum and warm to 70° Disperse the tn-
ethanolamine m the water, heat to 70° then
add to the melted oil phase with stimng Stir
Ull congealed Use a portion of the base to levi-
gate the ammomaied mercury then incor-
poime the remaining base
19 n
Sulfur 2 0
Phenol OJ
216 Semisolid Dosage Forms
Cct) I alcohol 80
While wax 05
Propylene ^ycol 50
Sodium lauiyl sulfate 1 0
Disulled water qs 600
Sig Apply to scalp as directed
Spectalty Emulsion Bases <o/w)
Almay Emulsion Base (Almay) — a hypo*
allergenic grcascless o/w base
Celaphil (Texas Pharmacal) — a water re-
movable grcascless base free from any fatty ma
tena] It contains cctyl alcohol, stearyl alcohol,
propylene glycol, s^ium lauryl sulfate and
water
Dermabase (Marcelle) — a hypoallergenic
grcascless emulsion base
Deemovia {Texas Phaimacsl) — an aetd pH
vanishing cream type of base compatible With
acid reacting medicaments The base consists
of glycciyl monostearate (acid>emuistfying),
spermaceti mineral oil glycerin and water
Mulubasc (At Ex)— a hydrophilic, nondehy
drating vamshing cream type base
Ncobasc (Burroughs Wellcome) — liquid pet
rolatum polyhydne alcohol esters propylene
glycol and water to form an o/w emulsion base
Phorsjx (Texas Pharmacal)— an o/w emul
Sion base made with oomonic emulsifiers The
base IS adjusted (o a pH of 4 6
Unibase (Parke, Davis)— noogreasy base
consisting of higher fatty alcohols, petrolatum
glycerin water and an emulsifying agent It
has a pH approximating that of the skin. Um
base will absorb 30 per cent of its own weight
of water
Vclvachol (Texas Pharmacal) — a hydrophilic
emulsion base compatible with acids, bases,
strong electrolytes and many other medica
ments The base contains cholcstcrin sodium
lauryl sulfate cetyl alcohol stearyl alcohol,
petrolatum, liquid petrolatum and water
WATER-SOLUBLE BASES
Tilts group of so-called greasclcss ointment
bases IS comprised of water soluble ingredi-
ents, the polyethylene glycol polymers known
as Carbowix* compounds Pojy ethylene Gly-
col Ointment USP is ihc_or^phannaCQ-
pocial preparation in this group Nilrofuto-
zone soluble Dressmg N F a a medicated
poly ethylene gly col sctnisolid preparation
The (^bowax compounds of mterest in
ointment formulation arc Uiosc that vary m
* Umoo Carbulc Chemicals Co , New York,
N Y
molecular weight from 1 000 to 6 000 ^n
sisiency of these compounds vanes from a
soft petrolatumlike semisolid to bard, waxy
soUds, the consistency mcrcasmg with mo-
lecular weight The outstandmg feaUirc of
these compounds is water solubihty fcitch
tests have shown the (Tarbowaxes to be m-
nocuous and no more irritating than lanolin
or petrolatum when applied to the skm ^
Cybowax. 1500, a soft, petrolatumlike
semisolid, can be used as a vehicle for the
topical application of medicaments However,
the higher molecular weight Carbowaxes arc
usually blended with the low molecular weight
(200-600) liquid polyethylene glycols for
oiDtment formahtioa For example, Poly-
cthy/ene Gfyeof Ointment C/S F is a blend
of Carbowax 4000 and polyethylene glycol
400 The base for Nitrofurozonc Soluble
Dressmg N F consists of a blend of poly-
ethylene glycols 300, 1,540 and 4,000
Polyethylene Glycol Omlment USJ* pos-
sesses many desirable properties It washes
off readily with water, il is not greasy, it
shows no physical changes on aging and it
permits ready dispersion oj water-soluble me
dicaments However, the solubility of this
base precludes the addition of aqueous solu-
tions much in excess of 5"pcr cent of the total
formula Inclusion of 5 per cent stearyl or
cetyl alcohol m the formula mcreascs the
water number of the omtment, allowing the
inclusion of 20 per cent of water
20 n
Burows soJutiDU 5 0
Polyethylene glycol ointment qs 300
Sig. Apply to irritated area three times
dmiy
The water solubility of polyethylene glycol
ointment precludes the inclusion of the Burow s
solution Replace 2 Gm. of the omtment base
with cetyl alcohol Melt the cctyl alcohol and
(he polyethylene glycol ointment on a water
bath Add the Burows solution and stir until
congealed
Medicaments such as benzoic and salicylic
acids, phenol and tannic acid have a solu-
bilizing effect on ointment bases containing
the high molecular weight Carbowax com-
pounds This may result in an undue soften-
log of the base These medicaments have been
ahown to mtcract with the high molecular
Weight polyethylene glycols, the complexes
formed having different solubility character-
Ophthalmic Ointments
217
isUcs from those of the parent compounds
In-vitro studies^® have shown that me-
dicaments diffuse readily from Carbowax
bases However, Shelmire*^ has shown that,
although diffusion of a medicament to the
skm s^ace from a polyethylene glycol vehi-
cle IS high, htUe percutaneous absorption
occurred. Michelfelder and Peck^® ako found
that a pol}ethylene glycol vehicle is not a
suitable vehicle for a water soluble drug, if
one desires percutaneous absorption
Carbowax compounds have been used to
prepare water removable emulsion bases to
which varymg quantities of water can be
added London and Zopf®^ developed the fol
lowing Catbowax emulsified base
R
Carbowax 4000
200
Stearyl alcohol
34 0
Glyccrm
300
Sodium lauryl sulfate
1 0
Purified water
ISO
Heat the Carbowax, the stearyl alcohol and
the glycenn on a water bath to 75^ C Add,
with stimog, to the water previously heated to
75° C and cootaming the sodium lauryl sulfate
Stir until the base congeals
Carbowax emulsified bases ore not truly
water soluble The Carbowax has an adjuvant
action as an emulsifier and improves the
water removability factor of the base In ad-
dition, larger quantities of aqueous solutions
can be added to such bases than can be
added to poljethylene gI}col vehicles
Polyethylene glycol vehicles form non-
occlusive films on the skin The residual film
from such bases can and will take up water
which has diffused through the skin or come
from the sweat glands, permittmg the loss of
such water to the environment. Since poly-
ethylene glycol vehicles do not maintam by-
drauon of the skin surface, it is understand-
able why water soluble medicaments are not
transferred readily to the skm surface.
Often included- m the group of _ymtcr-
soluble bases are scmisolid bases ^t ore
not soluble m water but swell with water
Such bases are hydrous and usu^y contain
an emulsifying age^t Included m this group
arc preparations produced throu^ the use
of bentonite, Veegum,* gelaun and cellulose
denvaUves Guth et al ® prepared bentonite
omunent bases m which vanous antibacterial
agents were incorporated. These omtments
showed high m-vitro activity
22 R
Bentonite
20 0
Sodium lauryl sulfate
05
Glycenn
100
Purified water
69 5
Sprinkle the bentonite on the liquid portion
of the base and stir at a slow rate of speed in
a mechanical mixer until a homogeneous prep-
aration results
Universal Omtment Base*
23 R
Veegum
100
Sodium lauryl sulfate
01
MelbyJparaben
01
Glycenn
100
Tween 80
10
Purified water
78 8
Add the Veegum to the water slowly, agi-
tating continually until smooth Add the other
mgr^ients, stu until smooth.
Massachusetts General Hospital Oint-
ment Base^®
24 R
Polyethylene glycol 200 mono
stearate
150
Veegum
SO
Polysorbate 80
10
Melbylparabeo
01
Punfied water
78 9
These bases are not greasy, spread readily
without rubbmg and form a protective film,
yet, they can be easdy removed from the
skm with water They do not alleviate dry-
ness as well as does petrolatum because they
arc not occlusive The residual film left on
the skm by these bases will take up water
which has diffused through the skm or come
from the sweat glands, hence, they arc vehi-
cles of choice when an omtment is to be ap-
plied to a moist lesion
OPHTHALMIC OINTMENTS
Special precautions must be taken la the
prcparati^^of an ophthalmic ointment The
active ingredient "is 'added to the''omtmcnt
base, “cither as a finely po wdered chemical
or as a solution. Wherc^ possible, the active
•R- T Vanderbilt Company, Inc., New York,
New York.
218 Semisoljd Dosage Forms
prcpanng light ointmcots or creams
(Hobart Manufactunog Company, Troy,
Ohio)
ingredient should bt. sterile as should 3 solu
lion of the active ingredient Not al) of the
dni^s prcscTjlvd in ophlhalmic oiniiTieats aiv
avadablc as sterile chemicals If available,
ampuls or vials of the dry parenteral powder
should be used However, although capsules,
tablets or the bulk chemicals may not be
stcnic they usually do not support bacterial
growth NMthm the lattice structure of the dry
material, hence they can usually be used
where the sterile powder is not available
Powders or tablets should be triturated and
incorporated m die ointment base aseptically
This can be accomplished by using sterile
utensils The mortar and the pestle, ^du-
ates, spatulas, etc , can bc_ycrilizcd by auto-
claving (a pressure cooker can be used) If
an omtment slab is used, it can be wa^ed
with an acuscptic solution (preferably by an
antiseptic dissolved in 70% alcohol) These
precautions arc necessary to prevent con-
taminants from infecting the eye, particularly
an eye which is already jnjured Ricgehnan
and Vaughn®* use the term ‘ mjured eje” to
mdicate one in which the corneal epithelium
has been damaged An_intact epithelial layer
acts as an effective bamer to orgapums which
mi^t otherwise invade the cornea Hence,
sterility is probably of greater importance
when the ointment is to be applied to an in-
jured eye than when U is to be_appUcd to an
intact eye (i c , one in which comeal cpi
thclium has not been damaged)
Most ophthalmic ointments are prepared
with a petrolatum base, a petrolatum mineral
oil base or a petrolatum wool fat base A
petrolatum wool fat base is sometimes used
when an aqueous solution of the active m
grcdicnt is to be incorporated jn an oph-
thalmic ointment Whatever type of base is
used, it must be nonimtating to the eye and
should permit dilTusion of the active ingredi-
ent from Uic base to the secretions of the
eye Although absorption bases, o/w emul
Sion bases and water soluble bases can be
employed for ophthalmic drugs, they may be
uTitating The irritation is probably due to
the surface active agent m the base At the
same time, the surface active agent may in-
crease the availability of the drug m the eye I
Petrolatum or a petrolatum mineral oil
base may be heat sterilized m a hot air oven
at 175® C for 2 hours After the active in-
gredient IS aseptically incorporated in the
stenie vehicle, the ointment should be trans-
ferred inio stenie ophtbaimic tipped tubes
The tubes can be stcniizcd by storage in 70
per cent alcohol for 24 hours prior to use
The use of tubes reduces the possibility of
contaminating the omtment
PREPARATION OF OINTMENTS
Mechanical Incorporation ^Vhcther an
omtment is applied to an irritated area of
the skin or to intact skm, it should be ho-
mogeneous, smootli and free from granular
or gntty particles The usual technic used by
the pharmacist to prepare such“an ointment
mvolvcs mechanical inco rporati on of the ac-
tive mgrcdicnt m the oimm_cnt base on an
omtment slab with a spatulx A mortar and
Preparation of Ointments 21?
a pestle are often used to incorporate liquids
in an ointment base. The mortar and pestle
are probably not as efficient as the ointment
slab an^ spatula for incorporating i^olu-
ble powders in an ointm ent base because of
the smalt'surface areajeyigated.at any one
time.
Mechanical incorporation of a medicament
on an ointment slab requires a ground glass
plate and two stainless steel_ spatulas. Hard
rubbe r spatulas or wooden tongue depressors
shouliTbe used when danger of chemical re-
action between the steel spatula and certain
medicaments, i.e., iodine, tannic acid, sali-
cylic acid, mercuric salts, etc., exists.
Before incorporating insoluble medica-
ments in aiTomiment base, the medicaments
must be reduced to an impalpable powder.
Fio. 78. Emcka equipment for oint-
ment preparation. {Left) Mixer and
kneader. (Right) Three-roller mill suit-
able for mixing and finishing ointment
materials in small batches. Motor unit b
detachable for all-purpose use. (Chem-
ical and Pharmaceutical Industry Co.,
Inc., New York, N. Y.)
This can be accomplished on a slab by levi-
gating the medicament w'ith a small portion
of the base to form a smooth nucleus. The
nucleus is then incorporated with the remain-
ing basej If very small amounts of medica-
ments are to be incorporated, a small amount
of mineral oil or a vegetable oil can be uSed
as a levigating agent . However, the use of
levigatmg agents (other than the base itself)
usually results in a marked softening of the
finbhed product. The details of preparing an
ointment by mechanical incorporation are
thoroughly understood. However, some me-
dicinal substances require special techm'cs
on the part of the pharmacist in order to pre-
pare a very smooth homogeneous product.
fAlkaloids can easily be incorporated in
ointment vehicles if used in the salt form.
The alkaloidal salt should be dissolved in the
smallest quantity of water possible. The aque-
ous solution can be incoiporated directly in
absorption bases, emulsion bases and water-
soluble bases. If an oleaginous base is pre-
scribed, the aqueous solution can be incor-
porated with a small quantity of \vool fat
before incorporating in the oleaginous bas£]
See Nos. 1 and 10.
Pilular extracts and other viscid materials
are more easily dispersed in an ointment base
if they are first softened with certain solvents
such as alcohol or chloroform. The amount
of solvent used should be kept to a minimum
220
Semisolid Dosage Forms
Fio 79 Roller mills such as (his arc
used m the large scale production of omt
menu (From Deno R A Rowe, T D
and Brodie D C The Profession of
Pharmacy Philadelphia Lippincott, 1959)
and the softened extract should be ini^r
porated immediately Diluted alcohol is used
ui the ptcpica^n cC Ouitio'ittX
N F and chloroform is used m the prepara
tion of Chiysarobm Ointment U 5 P
Coal tar can be incorporated readily u
oleaginous bases and pastes by first dispcrs
ing the tar with Polysorbatc 80 1/ 5 P , a non-
lonic surfactant The dispersed coal tar is
then incorporated in the base One per cent
of coal tar can be dispersed with 0 S per cent
of poi)sorbatc 80 Coal Tar Ointment US P
is an example of such a preparation Coal
tar usually can be meorporated m emulsion
bases such as Hydrophilic Ointment USP
by simple tnturation
Viscid matenals such as ichihammol and
Peruvian balsam arc only sli^tly soluble in
most oleaginous bases and, ^cqucntly, after
mcorporation m such bases, the ichthoounol
or the Peruvian balsam bleeds” or separates
from the base Both materials can be incor-
porated m an oleaginous base by first dis-
persing them m an equal weight of castor oil
Peruvian balsam and ichthammol can be in-
corporated m emulsion bases such as Hy-
drophilic Ointment US P with a minimum
amount of trituration
Fusion. Ointments co ntaining hard, waxy
ingredients such as wax, spermaceti paraffin,
Car]?Qwaxcs,Jiigh.jnokcular_wagh^aity al
cohols, etc , plus soft materials such as pelr o
latum and/or glycols, surfactants, watcr.»ctc ,
arc prcpar?d_by the fusion process This
process also can be used to incorporate me
dicamcntT* that arc readily soluble m the
melted base or to incorporate aqueous solu
tions in water soluble bases
In th ejusio n process ^e jngredicnt wijh
the highe^'melting point is piaccdln a bcaler
or evaporating dish and melted on a watef
bath The 'other ingredients ore added in
order of decreasing melting points jnitJ the
soft oleaginous matenals have all b een t hor
oughly incorporated Thfe^as e roust be sufred
until It congeals to prevent the Kparationpf
large particles of the ingredients with hipier
melting points. An active mgredi^t tha^ is
soluble m the base can be added to the warm
base }ust before it congeals Perfume oil^and
other volatile matenals should be added after
the base has cooled to about 35 to 40®_C
An active ingredient which is ins oluble, m
the base should not be spri nkled on th e
melted base Instead, the medicament shquld
be levigated with a small portion of the
melted base When the remaining base has
congealed it can be incorporated with^e
levigated mass
Emulsion bases are usually prepared by
fusion Waxes, fatty alcohols, lanolin and any
oleaginous matenals are melted in a suitable
vessel The emulsifying agent is dispersed m
the water, previously heated to approximately
the same temperature as the oleaginous phase
Any water soluble ingredients, such as pre-
servatives, and humectanis such as glyccnn
or propylene glycol arc dissolved m the water
The aqueous phase is added to the olcagmous
phase with stirring and the mixture is sUrred
until the base is congealed
25 li
Bismuth subnitrate 150
White wax 10 0
Packaging, Storage and Labeling of Ointments 221
Paraffin 5 0
Petrolatum 70 0
Sig Apply as directed
Melt the wax, the paraffin and the petrolatum
on a water base Use a portion of the melted
base to levigate the bismuth subnitrate on an
omtment slab Stir the remaining base until it
congeals, then combine with the levigated
mixture
26 0
Burow s solution 5 0
Poljethylene glycol 400 20 0
Polyethylene glycol 4,000 35 0
Sig Apply to irritated area daily
Melt the peg 4,000 on a water bath Add
the peg 400 and stir Add the Burow s solu
tion before the mixture congeals and stir until
the ointment congeals
Cetyl alcohol 8 0
White wax 0 7
Propylene glycol 5 0
Sodium lautyl sulfate 1 0
Purified water q s 60 0
Sig Apply to scalp as directed
Melt the white wax and the cetyl alcohol on
a water bath Disperse the sodium lauiyl sul
fate in the water previously heated to approxi
mately the same temperature as the cetyl alco-
hol wax phase and add to the wax phase with
sumng Stir until congealed Levigate the sulfur
with the propylene glycol, then combine with
the congealed base
PACKAGING, STORAGE AND
LABELING OF OINTMENTS
Fackagmg. Omtments are usually dis-
pensed m either omtment jars or tubes, jars
bemg used most frequently by the retail phar-
macist Omtment jars are available m brown,
green or opaque white glass
Ointments prepared by mechanical incor-
poration should be packed m jars uniformly,
to avoid air pockets A spatula can be us^
to fill the jar which should be tapped agamst
the palm of the hand dunng fillmg to ensure
that the air pockets are filled by the omtmcnL
The contamcr size should be such that the
omtment fills the contamer but docs not con-
tact the lid Imcr After the jar has been filled,
the spatula should be used to smooth the
surface of the omtment and give the product
a finished appearance
Omtments prepared by fusion can usually
be packed while the omtment is still warm
and fluid enough to be poured directly mto
the jar It is usually unnecessary to smooth
the surface of omtments packed m this
manner
The use of collapsible tm tubes avoids the
possibility of omtment contammation through
use Furthermore, a collapsible tube presents
a mmimum of omtment surface to the action
of air and hght Collapsible tm tubes are
avadable with special tips for application of
omtments to the eye, the nose, the rectum
or the vagma
Omtment tubes are easily filled by placmg
the ointment on a powder paper longer than
the tube Shape the omtment to form a cylin-
der shorter than the contamer Roll the cylm-
der with the paper to form a tube havmg a
diameter smaller than that of the collapsible
tube Slip the lube mto the contamcr then
flatten awut Vt inch of the open end of the
tm tube with a spatula Holdmg the flattened
edges of the tube together with the spatula,
grasp the protruding paper and slowly with-
draw it from the contamer This leaves the
omtment inside the collapsible tube Make
two */^ inch folds at the flattened end of the
lube to prevent any omtment from bemg ex-
truded The cap end of the tube should be
open dunng the process of fillmg and closmg
Storage. Ointments should be stored in a
cool place, primarily to prevent the base from
liquefying If the base should liquefy, insolu-
ble medicaments may settle to the Irottom of
the contamer Emulsion bases may separate
mto two phases if allowed to soften or liquefy
Water-contammg omtments should not be
unduly exposed to the air, since evaporation
of water may change the physical character-
istics of the omtment
When dispensing an ointment from a stock
contamcr, scrape the orntment from the sur-
face Diggmg mto the omtment exposes a
greater surface area, mcreasing the possibility
of rancidity, water loss and mold growth
Labelmg Special stnp-form labels, which
encircle the omtment jar or tube, are avail-
able Labels should be covered with cello-
phane tape to prevent soilmg
Labels are somewhat difficult to attach to
collapsible tm tubes Coat the area of the
tube to be labeled with benzom tmeture Per-
mit the tincture to dry and then apply the
222 Semisolid Dosage Forms
stnp-fonn labc! Labels should be attached
near the top of the tube to prevent dcstmo-
tion and soiling while the ointment ts being
used
OTHER TOPICAL PREPARATIONS
This section includes topical preparations
which do not fit easily mto the classification
of omtmcnts previously outlmcd Induded m
this group arc cerates, creams, pastes, plas-
ters and poultices These preparations differ
m consistency from ointments and are usually
medicated ^me i e , cerates, plasters and
pouluccs, arc spread on cloth before apply-
ing to the skm
Cerates are omtmcnlltkc preparations with
a consistency between those of ointments and
of plasters As the name implies, true cerates
always contam wax (cera) However, sper-
maccu, paraffin, suet or rosm have been em-
ployed as suflfenmg agents m cerates
Qrates are used by spreading at ordmary
temperatures on cloth and applying to the
skm They should not be soft enough to
liquefy when applied to the skin Cerates are
usually prepareJ with lard, oil or petrolatum
and a sufficient quantity of high melting wax
to give the proper consistency Because of
the high meltmg ingredient, cerates are pre-
K arcd by fusion (Hve cerates were official m
'F VIII Simple Cerate, Rosm Cerate,
Compound Rosm Cerate, Canthondcs Ce-
rate and Lead Subacetate Cerate
Cerates arc seldom presenbed in modem
dermatologic practice They formerly were
used as drnsmgs and protectivcs for mflamed
and ulceraUve areas of the slun
Creams are usually thought of as a soft
cosmetic type of preparation, i e , vaiusbiog
creams, hand creams, face creams, etc Phar-
maceutically, medicated creams arc scmisohd
or thick liquid emulsions containing medica-
ments dissolved or suspended in the emulsion
and intended for external applicaUon In gen-
eral. creams belong to the oil m water eroul
Sion classification of ointments However,
many preparations arc referred to as creams
because of consistency and appearance with-
out regard to the type of base used
In the Bntish Pharmacopeia creams are
medicated liquid emulsions consisting of a
mixture of wool fat, olive oil or other fixed
oil and hme water These preparations are
water in-oU emulsions similar to lime lim-
ment and calamine Imiment Tlic B P also
uses the term cream as a synonym for sev-
eml ointments and pastes
There is one cream official in NF XI,
Pramoxine Hydrochlondc Cream, It con
tarns PramoxmcHydrochlondcNF (Trono-
thane) • in a water miscible base Most pro-
prietary medicated creams are prepared with
water-soluble or water-removable bases
Pastes encompass two classes of omtment-
Iikc preparations for external use — the fatty
pastes such as zinc oxide paste and the non
greasy pastes containing ^yeerm with pec-
tin, gelatin, tragacanth, etc Pastes arc usu-
ally stiller and less greasy than ointments due
to a high proportion of powdered mgrcdients
such as starch, zme oxide and calcium car-
bonate m the base Powders may be present
to the extent of SO per cent, e g , Zinc Oxide
Paste VSP which contains 25 per cent
zinc oxide and 25 per cent starch m while
petrolatum
past es arc less greasy and niotc>absof|b
tiyc than ointments bccausc-oL theic^higb
proportion of powdered medicamenu haying
an affinity for water Therefore, they are pre-
ferred for acute lesions havin g aj endcacy
toward oozing, crustmg or vcsiculation Such
pastes are less pi.nctraiing and less macer-
ating than ointments and tend to absorb the
serous exudate Medicaments incoiporated
in pastes are absorbed less readily than from
ointments and, therefore, have a more super-
ficial acuon
In addiuon to powders, fatty pastes are
composed ol liquid jwtroiaium, pcuolatum
or fatty materials such as wool ht, benzoin*
ated lard, etc There arc three official fatty
pastes Aluminum Paste USP , Zme Oxide
Paste US P (Lassar’s Plam Zme Paste) and
Zme Oxide Paste with Sali^lic Acid SJ^
(Lassar's Zme Paste with Sali^lic Acid)
It
Zinc oxide
25
Starch
25
Calamine
5
Petrolatum q s
100
Sig. Apply as directed
Triturate the calamine with the zme oxide
* Abbott Laboratoncs, Chicago, Illmou.
Other Topical Preparations 223
and the starch and incorporate the powders in
the petrolatum A portion of the petrolatum can
be melted and used to tnturate the powders
Liquid petrolatum should not be used as a levt
gating agent, since the amount required would
result in softening of the product
29 B
Sulfur 1 0
Salicylic acid I 0
Lassar s paste q s 30 0
Sig Apply twice daily and b s
Levigate the sulfur and the salicylic acid with
a small amount of the base or with a very small
quantity of liquid petrolatum Incorporate the
remaining base Since the amount of medica*
tcient contamed ui this pcescciptioa w small a.
levigating agent such as liquid petrolatum can
be used
30 B
Ichthammol 1 0
Starch 25 0
Zinc oxide paste q s 60 0
Sig Apply at night
The second class of pastes, made with
glycenn and gelatin or pectin, are useful
when fatty bases are undesirable, i e , for ap'
plication to wet surfaces The nongreasy
pastes are advantageous when applied to
moist surfaces because of their miscibility
with water
Fantus and Dyniewicz^* introduced pectin
and tragacanth pastes for the treatment of
bedsores and ulcers The preparation of these
pastes and other nongreasy pastes differs
from the preparation of fatty pastes, since the
basic mgredient of the paste — pectin, (raga-
canth, etc — ^must hydrate In general, the
pastes can be prepared by hrst Vrctting the
hydrocoUoid with a small amount of glycenn
and then adding a sufficient quantity of hot
water
31 B
Pectin 5 0
Glycenn 10 0
Ringer s solution q s 60 0
Sig Pectin paste
Mix the pectin with the gljcerm. Then, while
stirring, add the Ringers solution previously
heated to 100° Continue stimng to mate s
smooth paste
Glyccrogelatm pastes are prepared by al'
lowing the gelatm to hydrate m hot water
and then adding the powdered medicaments
wdiich previously have been nibbed to a
smooth paste with the glycerin Glycerogela-
tin pastes soften at body temperature and
may be applied after they have been softened
by warming Zinc Gelatin U SP is a firm
glyccrogelatm paste It is used by placmg the
jar in hot water to melt the paste, which is
then applied to the skm with a brush The
paste congeals on the skm, forming a pro-
tective film
32 B
Zinc oxide
20 0
Calamine
20 0
Gelatin
100
Glycenn
100
Purified water q s
1000
Sig Apply to itching area
Add the gelatin to the water with stirnng
then heat on a water bath until the gelatin dis
solves Add the zinc oxide and calamine, previ
ously triturated with the glycenn Stir until a
smooth paste results
Nongreasy, water-dispersible pastes must
be stored in tightly closed contamers to pre-
vent the loss of water On standing for sev-
eral months, pectm pastes may liquefy The
liquefaction may be due to en^miatic hy-
drolysis of the pectm caused by mold growth
The parabens or benzoic acid should be em-
ployed to prevent mold growth
Plasters are sohd or semisoUd adhesive
masses spread on cotton, felt, Imen or muslm
and intended for topical apphcation to van-
ous parts of the body
The older type of plaster, prepared by
reactmg litharge and oil, was Imown as
diachylon plaster (Lead Oleate Plaster N F
IX) This type of plaster required the apph-
cation of heat m order to spread and apply
the plaster to the skm Plasters are now pre-
pared with a base of India rubber or with
mixtures of vmyl resm, plasticizers and other
chemical additives These plasters are ad-
hesi\« at body temperature and, hence, can
be applied readily without beatmg Further-
more, the newer adhesive plasters possess a
low^r mcidence of uritatioa and sensitization
than the older plasters which contamed such
mgredicnts as losm and pitch Plasters m
general may be somewhat irntant, partly be-
cause they prevent evaporation from the skm
and partly because of the small quantities of
224
Semisolid Dosage Forms
volatile ods contamed m the resms from
which plasters are often prepared
Years ago, the pharmacist prepared plas-
ters extemporaneously With the introduction
of machine made plasters, the hand-spread
plasters became obsolete However, the phar-
macist should instruct the patient purchasing
a plaster as to the method of applying The
part to which the plaster is applied must be
dry and dean to ensure close contact be-
tween the skm and plaster
The plaster serves two purposes (1) it
affords protection and mechanical support
and (2) it may be medicated, in which case
It bnngs medication mto close contact with
the sVin surface The demand toi mtdicavtd
plasters is limited to those containing sali-
cylic acid, belladonna and bclladorma and
salicylic acid and mustard Two plasters arc
official m the C/ J P Adhesive Waster (ad-
hesive tape) and Salicylic Acid Plaster, and
two arc official m the N F Belladonna Plas-
ter and Mustard Plaster
Poultices or cataplasms are soft prepara-
tions applied to the skin while hot m order
to reduce inflammation or, in some cases, to
act os countenmtants They apply moist
heat to the body areas and thcoreucally draw
mfcctious materials from body tissues The
drawing action is asenbed to the hygro-
scopic nature of the ingredients used as the
poultice base, i c , kaolin, flaxseed and other
mucilaginous substances The lost offiaal
poultice was Kaolin Cataplasm NF IX It
contained kaolin, bone acid, thymol, methyl
salicylate, pcppermmt oil and glycerin and
was used as a warming poultice for deep-
seated inflammations
REFERENCES
1 Blank, I H J Invest Derm J8 433,
1952
2 J Invest Demi 21 259, 1953
3 Proc Sci See. Toilet Goods Ass
2S 19, 1955
4 Blank, I H , and Shappino E. B J
Invest Derm 25 391, 1955
5 Barr, M , and Guth, E P J Am Phorm
Ass.lSci]-/0 13,1957
6 Blaug, S M , and Absan, S S Drug
Stand 28 95, 1960
7 J Am Phaim.As$ [Sci]50 441,
1961
8 Cospans, P , and Myer, E W Pharm.
actahelv 10 163, 1935
9 Chakravarty, D, Lach, J L, and Blaug,
SM DrugStand 25 137,1957
10 Oark, W G Am J Med Set 212 523,
1946
11 Cyr, G N, Skauen D M, Chnstian,
J and Lee, C O J Am Phaim Ass
(Sci]5S 615, 1949
12 Darlington, R C, and Guth, E P J Am.
Pharm Ass [Pract ] II 82, 1950
13 Fantus, B , and Dyniewicz, H J Am
Phairo, Ass [Sci ] 28 548, 1939
14 Flesch, P , and Esoda, E C J J Invest
Derm 28 5, 1957
15 Foster, W, Wurster, D E, Higuchi, T,
and Busse, L W J Am Pharm Ass
IScil40 123,1951
16 Goodman. H J Am Pharm Ass [Pract]
3 7, 1942
17 Halpern, A , and Zopf, L. C J Am
Pharm Ass [Scilid 101,1947
18 Higucbi, T, and Lach, J L. J Am
Pharm Ass [Sci ) 43 465, 1954
19 Johnston, G W, and Lee, C O J Am
Pharm Ass [Sci] 52 278, 1943
20 Jones. E R , and Lewicki, B J Am
Phann Ass [Sci] 40 509, 1951
21 Landon, F W, and Zopf, L. C J Am
Pharm. Ass [Pract)4 251,1943
22 Lane, C C , and Blank, 1 H Arch Derm
Sypb 54 497, 1946 and 54 650, 1946
23 Am Prof Phann 13 357, 1947
24 MacKce, G M , Sulxbcrger, M B , Herr-
mann F , and Baer, R K J Invest Derm
6 43,1945
25 McClelland, C P , and Bateman, R L.
J Am Pbann Ass [Pract] 10 30, 1949
26 Mall J W J Invest Derm 27 451,
1956
27 Malkinson, F D J Invest Derm 31
1% 1958
28 Meyers, D B, Nadkorni, M V, and
Zopf, L. C J Am Pharm Ass [Pract ]
32 231,1949
29 Michclfclder, T J , and Peck, S M J
Invest Derm 19 237, 1952.
30 Monasb, S J Invest Derm 29 367,
1957
31 Monash, S, and Blank, H A. M A
Arch Derm 78 710, 1958
32. Murphy, J T (cd ) Formulary of the
Massachusetts General Hospital and The
Massachusetts Eye and Ear Infinnary,
pp 91,92.94,95,1951
33 Peek, S M , Finklcr, B , Mayer, G G ,
and Michclfclder, T J J Invest Derm.
14 177. 1950
References
225
34 Peck, S M, and Click, A W J Soc.
Cos Chem 7 530, 1955
35 Plein, J B , and Plein, E M J Am.
Pharm Ass [Sci H2 79, 1953
36 Bull Am Soc Hosp Pharm.
13 38, 19S6
37 Powers, D H and Fox, C DrugCosmel
Ind 82 32, 1958
38 Riegelraan, S, and Vaughn, D G, Jr
J An Pharm Ass [PracL] 19 474, 1958
39 Rochow, E. G Chemistry of the Silicones,
ed 2 New York, Wiley. 1951
40 Rothman, S Physiology and Biocbem
istry of the Skin, Chicago, Univ Chicago
Press, 1954
41 Shelmirc, J B J Invest Derm 26 105,
1956
42 Arch Derm. 52 24, 1960
43 Stcigleder, G K , and Raab, W P J
Invest Derm 38 129, 1962
44 Strakosch, E. A . and Clark, W G Am
J Med Sci 205 518, 1943
45 Wuntcr, D E , and Kramer, S F J
Pharm Sci 50 288, 1961
46 Zopf, L C. Amencan Pharmacy, ed. 5,
p 315, Philadelphia, Lippmcott, 1960
chapter 7
Suppositories
Charles F. Peterson, Ph D.*
Suppositoncs arc solid, shaped unit dosage la VS P V and its use and the employment
forms for the apphcation of medication to of suppositoncs gradually increased
the rectum, the vaginal cavity or the urethral Suppositoncs are classified by the site to
tract Certam manufacturers refer to the last which Uicy arc to be applied and whether
two dosage fonns as “inserts,” particularly the medication is intended for local or s>s-
when made by compression as a specially tcmic effects The size and the shape of the
shaped tablet These melt or dissolve in the suppository are such that they facilitate m-
sccrelions of the cavity and usually release sertion into the body opemng Some manu-
the medication over a prolonged period For- facturers of ‘ inserts” furnish an apparatus
mcrly, specially shaped suppositoncs were designed to place the “insert” high m the
made to be placed in the ear and the nose vaginal tract or beyond the reach of the
Modern medical concepts for medication ap- fingers This type of preparation will be con-
plicd locally to these caviues calls for the ap- sidercd to be a special category of supposi-
pIicalioQ of a solution which is sometimes tones, since, in general, suppositories are
held in place with a pledget of cotton placed with the fingers mto the miended
The use of suppositories has been traced opening The pharmacist should make sure
to the time of the ancient Egjpiians and that the patient understands the correct ap«
Greeks ** Hippocrates recorded the use of phcation of the dosage form dispensed to the
herb and soap mixtures which were inserted patient
rcctally to sumulaie the defccaUon refiex when used without qualificauon, the terra
This use of suppositories appears in many of suppository usually signifies the form in-
thc WTitmgs S)stcmic absorption of drugs tended for rectal insertion The de-
did not appear to be important to these an- senbes rectal suppositories for adults as usu-
cicnts, although some mixtures coniammg ally wcighmg about 2 Gm each and having
potent drugs such as mandrake and poppy a tapered shape =* The most popular shapes
seeds were mentioned Perhaps the lack of a appear in Figure 80 Of these shapes, the one
suitable base and, consequently, of avaiJd- preferred by many is the modified torpedo
bdity of the acuve drug kept this dosage form on insertion of the blunt head, the pressure
from dependable use exerted on the suppository by the external
In the late 18th ccntuiy, cocoa butter be- anal sphincter is translated into movement
came available and Antoine Baumd rccog- which forces the suppository into the rectum
nized and promoted its usefulness as a sup- jj,g niodificd torpedo is formed most satis-
pository base in Europe In 1852, A B factordy by molding as m the fusion process
Taylor suggested the use of cocoa butter as cylindrical shape is more
a suppository base to American pharma- easJy attamed The largest diameter should
cists It was recognized as Thcobroma OJ 5 ^ about 13 mm , usually tapered to about
•Aswciaic Professor ol Pharmacy Temple Uni 7 mm , and the length about 25 to 35 mrm
versity School of Pharmacy For children, the diameter and the length
226
Suppositories 227
should be reduced, with accompanied reduc mucous epithebal surface m the vagmal tract
tion of weight to about 1 Gm is well supphed with circulation so 3iat medi-
Vagmal suppositories are more varied m cation may be absorbed and have a systemic
shape and usually have globular, ovoid or effect
modified conical shapes They are described Urethral suppositones (which may be
as weighmg about 5 Gm , but, on examma- called inserts ) are the form least used
tion, the majority of commerci^ vaginal sup- These are slender rods, 3 to 6 mm in diam
positones weigh between 3 and 4 Gm and cter, preferably somewhat flexible, yet firm
some weigh up to 8 Gm The vagmal sup- enou^ for insertion For the male urethra
pository IS used pnmarily for local effects, these are 100 to 150 mm long and for the
although It should be kept m mmd that the female 60 to 75 mm
Fig so Sizes and shapes of suppositones (Top) Rectal suppositories, 1 Cm
torpedo c>lmdncal tapered {Center) Vagmal ovals {Bottom) Vaginal balls and
pcssanes, with cross section (From Chemical and Pharmaceutical Co , Inc 90 West
Broadway, New York NY)
228 Suppos tones
THERAPEUTIC USES
Suppositoncs arc made primarily for local
cSccts of the medication and may be con-
sidered a solid umt dosage form of topical
preparations for special application The ac
tions of the medications mtroduced into the
rectum may be classified as follows
1 To stimulate the defecation reflex by
imtation
2 To soothe or heal the tissues immedi-
ately at the surface
3 To be assimilated mto the circulation
for systemic actions
The mtent of medications mtroduced mto the
vagnal tract is almost invariably that of local
action, therefore, the discussion of the im-
plications of the choice of base, the concen
tration of drugs and the intended duration of
action of medication will be m terms of the
rectum as the site of application
Smith points out that the ph)sician should
determine the state of rectal functionmg and
sensitivity of the patient for whom rectal
admmistraUoQ is contemplated
The function of the normal rectum u expul
Sion rather than rctemioo but there are indi
viduals whose lower bowel is quite tosensiuve
and habitually contains fcca] matter On
the other hand there are those whose rcctums
arc exceedingly sensitive, as in various forms of
proctitis and who would have difficulty retain
mg medicaments *
Local conditions such as anal Gissure or
inflamed hemorrhoids may also make rectal
administration difficult or dangerous
The advantages of rectal admmistration
for systemic eflects are (a) with some drugs,
this route is as effective as parenteral injec-
tion, (b) the stomach is not imtatcd further
in conditions such as cyclic vomiting, (c) the
drug does not come into contact with diges
tiie enzymes It is a convenient method of
administration for certain bed ridden pa-
tients, children and the mentally lU who re-
fuse to swallow Of interest to phaimaasts
and physicians is the possibility of controlling
the rate by which the drug is made available
for absorption-
Dosage. The problem of dosage limits rec-
tal administration It has been assumed that
• South, A Techtuc of htcdicaiion, p Il6
Ptuladelptua, Ljppiocott, 194S
the dose by rectum of some drugs is double
that by mouth On the contrary, the correct
dose and the rate of release of the drug from
the suppository must be delermmed for each
drug In some cases, the concentration of the
drug or the total amount of the drug which
must be given will be either too irritating or
in greater amount than reasonably can be
placed into a suppository The dose of 400
to SOO mg of a drug may be considered as
maximum, maLmg allowance for increasing
the weight of the suppository to 3 Cm In
any case, the availability of the drug from
the medication base is dependent on physical
characteristics of the finished dosage form
The suppositoiy base and the drug cannot be
considered separately because mixture of
drug with vehicle changes the physical prop
criies of the latter
As Reigclman and Crowell have shown,
diffusion of the drug to the surface for ab-
sorpuoD IS one of the rate limiting steps
They demonstrated the important effect of
particle size of the suspended drug and the
apparent effect of surface active agents on
the mucous fluid secreted over the absorbing
surface Another influence which can be
projected is the lowered availability of the
drug when it is bound to components of the
base either through physical interaction with
the surface active agents present or through
preferential solubility of the drug in the base
The effect of percentage of saturation on
the release of the drug from the solutions has
been thoroughly presented by AUawala and
Reigelman * The reasoning may be easily
followed that a drug that is very soluble m
theobroma oil and present m. a low concen-
tration will have a smaller tendency to escape
to the aqueous solution than will one that is
slightly soluble and present m the theobroma
oil at saturation level
The absorption of drugs from the colon as
described by Schanker'^ and the kinetics of
rectal absorption as determined by Rctgel-
man and CrowcIP® agree in principle, so that
It mt^t be said that the absorption of drugs
from the colon and that from the rectum arc
quite similar However, one should keep m
mind that the area to which rectal retention
enema is applied is much greater than that
of the suppository, since the latter mokes
contact only with ffic rectal ampullou The real
Testing of the Suppository 229
anatomic difference, with perhaps a physio-
logic advantage, is that the rectum is supphed
with the lower and the imddle hemorrhoidal
veins which pass directly mto the general cir-
culation The upper hemorrhoidal vein along
with venous supply for the digestive tract
pass mto the hepaUc portal system Thus,
medications and food products assimilated
m the alimentary tract circulate through the
hver before reachmg the general system
Drugs which are modified m activity or con-
centration by the hver are thought to act more
rapidly if they are spared immediate action
by the liver Bucher showed that more than
one half (50 to 70% ) of the rectally adnim-
istered drug was absorbed directly into the
general circulation ®
Drugs which are effective by proper rectal
a dminis tration mclude digitalis, chloral hy-
drate, paraldehyde, alkaloids, tribromo-
etbanol, hcxethal, thiopental, certam bar-
biturates and theophyllme The factors which
mfiuence availability from the rectal colon
area include the degree of lonizauoo and the
lipid water partition of the undissociated
form The pH of the colon was demonstrated
by Schanker*^ as 6 8 to 7 0, and it was found
to have little buffer capacity Thus, the dis-
solved drugs contained m the area will de-
termine the existing pH according to their
o\vn properties of dissociation Therefore,
weak acids and bases are absorbed, while
those which are highly lomzed are absorbed
slowly Schanker further showed that acidic
drugs were absorbed more readily when the
rectal contents were made more acidic Weak
organic electrolytes that are highly lipid solu-
ble were found to be absorbed more readily
TESTING OF THE SUPPOSITORY
The US P XVI m its defimlion of sup-
positories states that the preparation should
melt, soften or dissolve at body tempera-
ture -* Also, on page 4 of the General Notices
sccUon of the USP under Ointments and
Suppositories there is the statement “the
proportions of the substances consutulmg the
base may be \aned to mamtam a suitable
consistence imder different climatic condi-
tions, provided the proportion of active
mgredients is not varied ” The official pro-
of a degree and a scale ranging from 32
to 45* is adequate (Setnikar, I, and
Fanlelh, S J Pharm Sci 51 566 571)
cedure for determmmg the melting tempera-
ture of fatty substances (Oass II) can be
used to determme the meltmg range of the
simple suppository, but it docs not prove to
be satisfactory for those suppositories con-
taining a significant amount of suspended
particles Nor is the meltmg procedure satis-
factory for the definition of “softening or dis-
solving at body temperature ”
Setnikar and Fantelh*® have recently re-
viewed the proposed methods for descnbmg
the physical properties of suppositories and
have suggested an improved test procedure
This procedure for hquefaction tune appears
to answer many of the problems not previ-
ously solved by any one procedure A com-
parison of the liquefaction umes with the
clmical experiences should be made, as was
done by Hennig,® to make the results of this
test significant
Setnikar and Fantelli desenbed the me-
chanical and the ph}sicochcmical conditions
present m the human rectum which they
thought important for a test procedure to
reproduce These were (a) an average tem-
230 Suppositories
Table 33 A Comparisos of Melting Pojmt* and Liquefaction TiMEf
SupposnoRY
Base
Melting
Point
(“C)
Liquefaction
Time
(Minutes)
Composition
Tbeobroma Oil
34
6
Disaturatcd triglycerides
Estannum At
37
9
Modiiied coconut oil with added mono*
Estannum Bt
38
30
glycerides
Imhausen E§
38 5
If
Hydrogenated tnglyccndcs of launc acids
imhausen H§
36
9
plus monoglycendes
Dcbydag III#
39
11
Hydrogenated tnglyccndcs
Carbowajt 1 540 ••
46
18
Polyethylene glycol (number represents
Carbowax 4 OOO*^
59
30
average molecular weight)
Carbowax 6 000* •
Carbowax 6 000 +
62
45
20% water* •
54
27
ClycennalcJ Gelatin 50
32
50% Gelatin and gi)ccnn
Myr] 52tt
51
31
Polyethylene glycol monostearate
Tween 61+'*^
39
II
Polyethylene glycol sorbitan monosCearaCc
* Method of Bogs
t Measured at 37'
P/ arms, e 1958
• C
121
t Edelfctiwerke Hamburg Eidclstedt, Germany
HmhaiuenCo WiUen Ruhr Germany (now Wuepsol Chemische Werke)
[| Softening after 10 to 20 minutes no Uquefactioo during I hour
# Deutsches Hydnenverke Dusseldorf Germany
••Union Carbide Chemicals Co New York 17, N Y
ft Allas Chemical Co Wilmington 99 Delaware
(Adapted from data of Setnikar I and Fantelli $ Liquefaction time of rectal suppositones
; Phann Sci 51 566 )
pcrature of 36 9“ C (36 2® to 37 6® C ), when the suppository has completely melted
(b) water not present in the liquid state but A comparison of meltmg points and hque*
represented tn the semisolid fcccs (which faction times of some suppository bases is
contain about 80% of water), (c) water given m Tabic 33 Mor(^,detai]ed composi-
content somewhat variable due to dilTusioa Uons for the suppository bases ace listed m
from the body fluids (osmotic force attracts Chapter 19 of American Pharmacy, 5th
(he water and high force may result in im- Ediuon
tation and pain), (d) practically no peris-
taltic movement, (c) pressure on the con SUPPOSITORY BASES
tents varying from zero to 50 cm of water,
and (f) possible presence of feces In suppositories, the function of materials
Tlie apparatus (Fig 81) is prepared by other than medication is to present an accept-
placing a length of moistened inflated ccJlu- able and usable dosage form For example,
lose dial}sjs tubing through the cylinderand the difficulty of handling a rectal cvacuani
over the ends, securing live end of the tubing dose of gljccnti is overcome by the addition
with clastic bands Water is circulated through of soap to make a Arm gelled mass which can
the cylinder and the height of the apparatus be inserted readily The suppository base also
adjusted so that the lower half of the tubing may be required for dilution of the drug to a
is collapsed When the temperature of the nonimtating concentration Tlius, the im-
watcr has been adjusted to 37“ C , the sup lant local action and the volatility of chloral
pository IS dropped mto the open end of the hydrate arc reduced to acceptable levels by
tube Then the apparatus is lowered about incorporation into a suppository Other pos-
30 cm to obtain the desired pressure of siblc functions of the base are to stabilize or
water The liquefaction time is determined to control the rate of release of the drug This
Suppository Boses 231
may be demonstrated by the following ex-
ample The poor dissolution rate of aspinn
from a compressed form and its consequent
slow rate of assimilation may be obviated by
use of a suppository preparation containmg
a dispersion of finely powdered drug in a
suitable base
A general classification of suppository
bases is possible on the basis of their physical
properties The oleaginous class includes
cocoa butter and fats with similar properties
and contrasts with the ‘ water-soluble” class
which includes the polyethylene glycols and
glycero gelatin An intermediate ‘ hydro-
philic” class IS proposed to include all
those not moluded m the other two as •weW
as those surfactants and mixtures which dis-
perse themselves or the medication in water
Theobro-na oil (cocoa butter) is the prin-
cipal suppOiitory base and is often thought
of as the base to be used when none is speci-
fied It IS 3 firm solid of cream color which,
on warming, begins to soften at 30** C and
melts to a thin oil at about 34’’ C Unlike
many fats and oils, cocoa butter is generally
uniform, having a faint, agreeable odor Its
composition is also difierent in that there are
only a small number of glyceride types pres-
ent and two of these constitute more than
three fourths of the total Meara** repotted
the composition of one representative sample
of cocoa butter to be as follows
Mole
Percentage
Fully saturated tnglycendes
26
Olei^ipalnutin
37
Oleopalmitosteann
57 0
Oleodistearm
22 2
Palmitodiolem
74
Stcrodiolem
58
Tnolein
1 I
Ajconsequence of the prr^en cy of the higb
pro portion of disaturated triR lyccndes is
n mrked p^vmorphKm (the property of exist-
ingm several crystalline forms) When cocoa
butter is heated to above the melUng tem-
perature (about 36'^ C ) and then ch^ed m
a suppository mold, solidification does not
take place until the temperature ts well below
1 5° C_ and crystallization takes place as a
metastable form. If such a suppository is
taken from the mold after such treatment
Fic 82 The per cent of drug released
from cocoa butter after 90 minutes as
related to the temperature of the test
Abscissa temperature in °C (Sprowls,
I B American Pharmacy, ed S Phila
delphia, Lippmcott)
and allowed to come to room temperature,
It will be found to melt at about 23° or
24° C The explanation of this phenomenon
IS that the stable ciystal nuclei have been lost
by heating the cocoa butter beyond the melt-
ing point Should the suppository made from
the overheated cocoa butter be allowed to
remain cool for a sufficient length of time,
its original melting temperature will be re-
stored The exact length of tune will vary
from a few days to more than a week accord-
ing to the response of the melted mass to the
rate of cooling and the presence of other
components Should it be necessary to heat
cocoa butter, the melting should be done
carefully, keeping temperature of the mass
as low as possible and mixing well to keep
the temperature uniform The finely shredded
fat IS heated carefully to a creamy, pourable
State, leaving nuclei of the stable crystals
which, on cooling, encourage solidification
to the onginalform
A further complication results with cocoa
butter suppositories when substances dissolve
significantly m the fat and lower the melting
temperature It is well known that the frccz-
mg point of a solution is lower than that of
the pure sohent and the freezing point de-
232 Suppotitones
pression ts proportional to the conccntratioQ
of the solute The proportionality constant
IS the molal freezing point depression which
IS estimated as IS** to 16° C for cocoa
butler •
Increasing the concentration of a soluble
substance m the fat lowers melting tempera*
turcs of the mixture until the eutectic point
ts obtained Further addition of the sub-
stance increases the melting temperature
from the eutectic point up to the meltmg
point of the added compound Thus, the ad-
dition of white wax to the cocoa butter in
amounts up to 3 per cent will gi\e mixtures
which have lower melting temperatures than
the origmal cocoa butter (even after appro-
pnatc agmg) Addition of white wax beyond
6 per cent is required to raise the melting
temperature of the cocoa butter-wax mix-
ture Even larger proportions of wax will be
required to make an acceptable suppository
should other soluble components be present
m amounts having a significant elTcct on the
melung temperature
The addition of a greater number of com-
ponents may also have the effect of increasing
the melting range The suppository may have
a liquid portion held by the crystollme matrix
at ordinary room temperatures On warrnmg.
additional components become melted unul
a significant portion has been melted and the
solid form no longer exists Thus, the meltmg
point of the base is most significant when the
medication is not appreciably dissolved m
the base but is merely suspended in it Fig-
ure 82 illustrates the availability of anuno-
pynne and procaine hydrochloride from
cocoa butter ut aw iw-vitro test os reported
by Eckert and Muhlcman
In detenrunmg these data, the procamc
hydrochlondc was suspended in the cocoa
butter as a fine powder It is evident that
*This value was calculated from the mcltiog
point determinations reported by Oeschi^ for dilute
concentrauoas (about DOS molal) of phenol and
procaine. The value 6* C staled in Amencan
Pharmacy (5lh ed.) was calculated from the
determination of 20 per cent Chloral Hydrate
(about i 2 molal) in cocoa butter The higher cou
ceniraUon of solute as used in the latter case
causes departure from the “ideaP solution and it
has been suggested that mlerpretalioa of these
lowered melung poinu should be made using the
concepts of cutecUc formauon by phase diagram
analysis.
the procaine was able to transfer to the oil-
water mtcrfacc after the temperature bad
reached the melting temperature of the cocoa
butter The ammopynne was released to the
water and did not appear to be more than
sli^tly tcmpcraturcAicpendcnL It may be
assumed that the aminopynne was dissolved
m the liquid portion of the suppository base
and was transferred by diffusion to the oil-
watcr mtcrfacc
Fatly Substitutes A number of olcagmous
substances have been suggested as subsU-
tutes for cocoa butter Most recently the use
of lUipe butter, or Borneo tallow, has been
proposed This vegetable fat, because its
melting temperature is slightly higher than
that of cocoa butter, may be used more con-
veniently The German Pharmacopoeia in
1959 recognized Adeps Sobdus in its Third
Supplement to the 6ih Edition * The mono-
graph bearing this title desenbes neutral fatty
compounds contaixung triglycerides of satu-
rated vegetable fatty acids mixed with partial
glycendcs m various amounts to control vis
cosity and emulsifying abiii^ of the base (see
Table 33, p 230) A number of items stmilat
to Adeps Solidus arc now available in the
United States and include the Wcccobee
senes* and the Witcpsol senes t These bases
arc reviewed by Pcnnaii and Steiger Tnppi
In general, oleaginous compounds of the
types described are used in the same way
as cocoa butter, however, they have an ad-
vantage m that the formation of unstable
polymorphic forms with lower melting points
docs not take place easily They have in-
creased ability to emulsify water and glyc-
enn and arc stable to oxidation However,
Hennig* and others have shown that drugs
arc absorbed at diUcrcnt rates from these
bases and from cocoa butter Therefore, this
IS another mdication of the need for clinical
companson of results, as opposed to reliance
on m-vjtro data
Water-Soluble Suppository Bases
Glyccnnatcd Gclatm. The general for-
mula and procedure for mabng Glycermatcd
Gclatm Suppositoncs arc desenbed m US P
XVI and may be outlmcd as follows:
• Drew Chemical Co
t Riches Kelson, Inc. New York, 17, N V
Suppository Boses 233
Table 34 Physical Properties of Selected Polyethylene Glycols
FOR Suppository Use*
Series No
Average Freezing
Molecular Specu=ic Range
Weight Gravitv " C,
Solubility at 20® C
(Gm per 100 ML )
Water Methanol Ethanol
300 (N F )
300
1 125
—15 to -8
completely miscible
400 (t/-S P )
400
1 125
4- a
completely miscible
1,500
t
1 15
38-11
73
48 1
1 540 (WF)
I 450
I 15
42-46
70
4,000 (USP)
3,350
1 204
53-56
62
35 1
6,000
6,750
s
60-63
§
20,000
17 500
§
53t
§
• Abstracted from Carbowax” Polyethylene Glycols, Union Carbide Chemicals Corporation, 1958
t Mixture of equal parts polyethylene ^ycol 300 and polyethylene glycol 1,540
t Softening point reported because of the high viscosity of the melt
§ Data not available
Water and the medicinal agents 10 Gm
Glycerin 70 Gm-
Gelatta 20 Gm.
The ingredients are mixed m the order in
which fiiey have been given, taking particu-
lar care that the medication is dissolved and
the gelatin added without formation of lumps
or mcorporation of air So^ation of the gela-
tin requires heat and time Tice” suggested
that a salt-wa^ bath be used to increase the
temperature and^feduce the. tune for the
gelatin to dissolve If an electric hot plate is
used, care must be taken so that the high
temperature docs not cause the mixture to
bum, especially since the glycero-gelaim mix-
ture does not conduct heat readily from the
bottom to the rest of the mixture The mass
should be well stirred, but with care that air
bubbles are not entrapped Either Pharmagel
A or Pharmagel B may be used to make the
suppositories, accordmg to the compatibili-
ties of the medication Propylene glycol or
Polyethylene glycol 400 may be used to re-
place the glycerin for drugs requiring such
solvents Sometimes the gclalm content is in-
creased to as much as 30 per cent to make a
firmer suppository, especially when it is to be
used for rectal insertion
■At Gl ycenna t ed gehtuiJ?ase_is _most ^icn
H-^ setf for local application of a ntibacterial
agents to the vagmiJ^ct whe^ e it is m t end^
that the solutioiTbc re tain^ for prolonged
action of thc^djug Th^hygrosco pic te ndency
of the gljcena mi^es it new^sary lhat_ihc
suppository be protected from externa l mo is-
mr6.and, auhe sam e time,jeqmrc5 sufiBcient
water to be present m the glycennated gela-
tin suppository to preyenljintati on of th e
mw^us tissues I t is recommended t hat the
glycennated .gelatin suppositor y_be mo is-
teo^ jvilh water, before msertign^O^®
a wayjh ^mijjal “sting®® caused by the b^gro-
scopic'agent
The polyethylene glycols were developed
m Germany dunng the 1930’s as the result
of the need for “ersatz” matenals They were
patented m the United States and Germany
m 1938 as water-soluble ointment and sup-
pository materials* The sobd polyethylene
glycols have molecular weights above 1,000
(as shown m Table 34) The viscous solu-
tions formed when they are used are less
bkely to leak from the body cavity to which
they have been applied As is the case with
glycennated gelatm, water must be com-
pounded in the suppositoiy or the sup-
positoiy dipped m water before msertion in
order to overcome the possibility of irnta-
Uon caused by water being drawn from the
tissues to dissolve the base and release the
medicament. Foimulaiors have suggested the
use of a coating contaming a local anes-
thetic, and another suggestion which has
been made is to include a waxy material such
as cctyl alcohol The former suggestion adds
therapeutic complication and the latter sug-
gestion makes a product that is dissolved
slowly The problem of imUUon is empha-
sized m the arguments against the use of ^cse
bases, whereas the proponents of the use of
234 Suppositories
Table 35 Polyethylene Glycol Suppository Bases
Base No
1
2
3
4
5
6
7
Polyethylene glycol 400
30
Polyethylene glycol 1 000
96
75
Polyethylene glycol 1,540
33
30
70
30
Polyethylene glycol 4 000
33
40
4
25
Polyethylene glycol 6,000
47
47
30
50
Water
20
20
20
Bases Nos 1 anJ 2 from SperanUio G J , and Hassler, W H J Am Pharm Assoc (Pract ) 14
26 1953
Base No 3 from Hassler W H and Cacchillo A F J Am Pharm Assoc (Sci ) 4J 683, 1954
Bases No 4 through No 7 from Collins A P, Hohman J R., and Zopf. L C Am Prof
Pharm. 23 231 1957
the base find that imtation is a minor consc*
qucncc There is reason to believe that the
level of iiTitatiOQ will vary with individuals,
medications, formula modifications and con-
diiions of use
Cacchillo and Hassler^ reported that the
2*hour blood salicylate level after adminis-
tration of acetylsalicylic acid averaged as
follows water-soluble suppositoiy, 93 per
cent of the level after oraJ administration,
cocoa butler suppository 66 per cent and
glyccro gelatin suppository, 53 per cent
Spcrandio and Hassler’* compared the poly-
ethylene gl)col base with cocoa butter by
making suppositories of water-soluble bar-
biturates and determining the onset of action
and the duration of action in rats The onset
of barbiturate action was more rapid from
cocoa butter suppositories and the duration
of action was longer from polyethylene gly-
col suppositories
Some examples of formulas proposed for
polyethylene glycol bases will be found in
Table 35
As these formulas mdicate, considerable vari-
ation IS possible IQ the proportions of high
molecular weight and low molecular wei^t
polyethylene glycols to be used With certain
drugs It may be possible to use a single solid
polyethylene glycol
Difficulties m compounding are usually re-
duced by mixing several of these bases to
yield the desired properties An example of
the difficulties encountered is the formation
of a gclatmous mass which occurs when aim-
nophyllmc is melted with polyethylene glycol
4,000 (Guida) ' Addition of 10 per cent or
more of the lower molecular weight poly-
ethylene glycols 400 or 1,500 facilitates for-
mulation by retarding the gel formation dur-
ing the melting stage so that the mass may be
poured mto the suppository mold Addition
of the low molecular weight polyethylene gly-
col compounds and water aid m the forma-
tion of a more plastic mass, however, these
compounds may lose water unless the more
hygroscopic glycerin or propylene glycol is
added A hnn plastic property is desired to
prevent formation of a crumbly mass A large
proportion of insoluble medication or use of
the higher molecular weight polyethylene gly-
cols (particularly polyethylene glycols 4,000
and 6,000) may lead to the formation of a
dry crystallme mass that is easily crumbled
The “hydrophilic” suppository bases as
defined m this chapter arc those mixtures of
the oleaginous and the water-soluble mate-
nals which make suitable mixtures, which
emulsify water to make w/o emulsions or
which disperse themselves m water Ex-
amples of suigle substances that are mcluded
m this class arc PoJycuyJ 40 Stcaxalc fMyij
52*) Polyoxyethylene sorbitan monostcarate
(Tween 61*) and Polyoxyethylene oxy-
propylcnc stearate (G2i62*)
Mixtures of cocoa butter with various
emulsifying agents have been made It is
relatively easy to add 2 per cent of choles-
terol or 10 per cent of wool fat to cocoa
butter, which will allow the incorporation of
a significant proportion of water (up to
25%) in the form of a w/o emulsion. It is
difficult to sec how a true o/w emulsion sys-
tem may exist m a solid dosage form that
*AUas CbenuciU ladiutnes, Wilmington Dela-
ware
Methods of Manufacture 235
would be suitable for suppository use The
external continuous phase should be of a
sohd or semisolid matenal that melts or
dissolves
Mixtures of oil emulsifying agents with
fatty bases must of necessity produce a_lquasi
emulsion”“to form a solid suppo sitory O n
contact with the mucous fluids, they are hy -
drated to form a creamy fluid which spreads
over the cavity and m time relies the basic
medicaUon There is insufficient m vivo"data
available to confirm this, but m vitro release
data by EckerTand Muhleman^ mdicate that
water-soluble drugs dispersed in w/o emul-
sions axe not as readily available as the same
drugs suspended in anhydrous vehicles
A great deal of caution is advised in the
use of surfactants with drugs intended for
rectal absorption,’ ^ since there are
many reports of mletactions of these com
pounds with active drugs Each combmation
should be considered on its own ments and
clmical testmg is indicated for assurance of
therapeutic efficacy
Tardos er a/ “ have reported increased
absorption of atropine sulfate, morphme sul-
fate, pilocarpine hydrochloride and peoia-
methazol as measured by a pharmacologic
test when cocoa butter base was modified by
the addition of Span 60* at 3 per cent or
Tween 60* at 1 per cent With atropine sul-
fate it was reported that the addition of mtro-
glycenn 0 01 per cent or 0 05 per cent fur-
ther increased the pupillary response Usmg
suppositories without the surface active
agent, no increased response was observed
on the addition of the local vasodilators
METHODS OF MANUFACTURE
The method of manufacture of supposi-
tories depends on the number of units to be
made, the materials to be used and the equip-
ment at hand In general there may be con-
sidered to be two methods — the hot or the
fusion process and the cold process All of
the suppository bases and many of the added
medicaments can be processed by melting
the mixture and pourmg it mto molds The
cold process may be subdivided further into
•Alla* Chemical Imiustnes, Wilmingloa Dela
ware.
the hand rolling method and the compression
method, which differ m the manner in which
the suppositories are formed
The hand rolling method is the molding
o f the si^po^tory with the finprs af^r the
formatio n of a plastic m ass This method has
I he advanta ge of requirmg only the mmimum
of^^ipment— a'mortar and a pestle, a spat-
tila and a piH tile o^afo inimenrslab Usu -
all y no more th an ^_or l2~dos es'^re m ade
at one time by this method and no excess of
ma tena ls need.be. m^is ured, smcei!^ith.good
technic, tl^ lo ss of m ateria ls will be sli ght
Th^powdered_jnedicatioiL is mixed in a
monar, wlh a peslie wnb an equal amount
of finely grate d cocoa butter In orde^to
ensum a uniform mass, the rest of the finely
divfded cocoa butter is added a little at a
time and the mass is mixed thoroughly after
each addition The pes tle should be used to
force the mass against the sides of the mortar
and cause the lumps of cocoa butter to be-
come partly liquid Should the mass fail to
becom^plastic, it may be transferred to a
mortar warmed by application of hot water
(about 30* C is the maximum allowable
temperature for the mass) Suppository mix-
tur es containin g a large amount of insoluble
powders (10% or more) may require_thc
addition pf _a bland vegetable oil (cottonseed
or peanut od) to the extent of about one
half the weight of the powders
The uniform semiplastic mass is taken
from the mortar and placed onto a sheet of
lioticss paper towel or filter paper so that it
can be kneaded by hand Bykecpingthepapcr
between the mass and the hands, the ^gers
do not come in contact with the mass which
IS being kneaded Better results are obtained
by rapid, continuous kneading than by work-
mg the mass so slowly that the liquefied por-
tion of the cocoa butter has a chance to revert
to the normal solid form
Once the cohesive plastic mass has formed.
It can be rolled out on the pdl tile into a urn-
form cyhnder having the same diameter as
the suppository to 1^ formed The cylinder
IS divided into the number of suppositories
to be made At all tunes, the mass is handled
with the spatula directly or with a thickness
of paper between the fingers and the sup-
pository mass The umt portions of the cylin-
236 Suppositones
dcr are shaped quickly mto the desired form
of the suppository, since the mass quickly
solidifies and loses its plasticity (Fig 83)
The conical shape and the pointed cyfiodcr
are shapes made more easily than the modi-
fied torpedo shape previously described Uni-
formity of weight, shape and length may be
checked visually and by measurement Ap-
pearance IS important for the sake of the pa-
tient, who may prejudge the efficacy of the
medication by the neatness and the uni-
formity of the medication
The finished suppositoncs will regam much
of the firmness observed m the ongmal cocoa
butter when they arc allowed to stand for a
penod of hour or so Usually, they are
not packaged until after such a coolmg period
m order to prevent the deformations which
would otherwise occur in wrappmg and plac-
mg mto a carton
The compression method requires the for-
mation of a uniform mixture pnor to plac-
ing the mass into the chamber for molding
One should follow the procedure desenbed
m the previous section for makmg the urn-
form mixture of medication with cocoa but-
ter In this method, three or four additional
suppositories must be made for each lot so
that excess material is available to expel the
suppositoncs from the mold
First, one must find the weight of the base
for each suppository This is done m the fol-
lowing manner (assuming cocoa butter as
the base)
The cocoa butter is placed in a granulated
form m the chamber of the machine to which
the appropriate mold has been attached
Molds arc available for S-Gm vaginal and
for t-Gm or 2 Gm. rectal suppositoncs The
compression chamber is placed m the frame
and the pressure wheel turned to dose the
djamber Then crushed ice is placed on the
chamber and the mold for a few minutes
After dulling the mass to approximately
10* C , the pressure wheel is turned to ex-
trude the base from the chamber mto the
mold against the end plate After the air is
expelled from the base, there is a considerable
mcrcasB m pressure on the wheel At this
point the pressure wheel is reversed slightly,
the end plate removed and pressure re applied
carefully to eject the molded suppository
The trimmed suppository is weighed to de-
termine the weight of the cocoa butter needed
to fill the mold
The novice is advised to read the operating
instructions for the compression machme and
to make a practice lot usmg plain cocoa but-
ter The temperature of the compressed mass
IS the cniical factor for case of manufacture
Under pressure the matenal will fiow mto the
mold, solidify and contract sufficiently when
not under pressure to be ejected m solid
form For plain cocoa butter this tempera-
ture range is about 5® to 10® C The tem-
peratum range must be increased for those
masses containing significant amounts of m-
soluble powders and reduced when materials
lowering the meltmg range of Che mass are
present
Many of the suppository bases proposed m
this chapter may be formulated with drugs
and excipients permitting the use of the com-
pression method. The mass should have suffi-
cient plasualy to how mto the mold under
pressure and to congeal when the pressure
IS removed so that a solid form may be
ejected The use of plasticizing agents and
coDlroJ of the teofpcTature for compressjoa
make the use of many other matenals
possible
The fusion method is used with all of the
suppository bases and may be used for all
but the most heat sensitive drugs It is the
method used for making gelatin base sup-
positoncs and Glyccrm Suppositoncs, US P
because each of these matenals requires a
high temperature Also, the suppository for-
mulas using a polyethylene glycol base quite
often are prepared by melting all constituents
together and pourmg the liquefied mass di-
rectly mto the mold The molds are usually
at room temperature or lughcr if a slow rate
of cooling IS required to allow air bubbles to
Fic 84 The Armstroog Suppository Machine No 3 (formerly knows as the Whitall-
Tatum Press), showing compression chamber, separate dies, end plate and locking wrench
(Armstrong Cork Company, Lancaster, Pa.)
nse to the surface and, thus, aid in formation
of a more stable form
In the procedure for cocoa-butter-basc
suppositories, only enough heat to cause the
mass to become pourable should be used
Fio 85 Pounng of Suppositoncs
(Witepsol, Chcmische Werkc Wilten,
1961)
Insoluble powders may be mixed with grated
cocoa butter m a mortar with a pestle, or a
portion of the melted mass may be poured
as a levigation agent on the powders while
they are mixed with the spatula on an omt-
ment slab Once a smooth mixture has been
made, the mixture of powder and base is
placed in a beaker to be melted with the
remamder of the base The mixture is stirred
Fig 86 Suppository mold having longi-
tudinal partition. (Witepsol, Chcmische
Werke Witten, 1961)
238 Suppositories
Fjc 87 Suppository mold of transverse
partition design, closed (Witepsol, Che
miscbe Werke Witten, 1961)
to prevent settling of the powders as it is
poured into the cfiilTcd mofrfs The mofds
should be overfilled by 3 to 4 mm to allow
for contraction on cooling One should expect
the formation of a dimple in the center of
the molded suppository, as suppository ma-
terials contract on solidification and, thus,
allow convenient removal from the molds
Comparison of Methods of Manufacture.
Reports have been made from time to tunc
of variations in absorption of drug caused
by the use of different procedures Tardos
et al ■' reported a difference between sup-
positories made by the compression method
and those made by fusion for two of the
bases tested (Myrj 52 with Carbowax) “The
differences may occur because the drug is not
solubilized or dissolved m the excipient when
the suppository is made by mixmg and com-
pression Gunnar Hopp'“ compared melted
and compressed suppositories, for those sup-
positories made by compression he reported
increased oxidation which he atlnbuled to
mcraJ from itic mschiac entering the sup-
pository and acting as a catalyst to oxidative
changes Many of the suppository bases arc
subject to such oxidative changes, and, there
fore, care should be taken particularly to
avoid iron contamination
SPECIAL DISPENSING AND COM-
POUNDING PROCEDURES FOR
SUPPOSITORIES
Incorporation of Insoluble Powders. Pow-
dered material should be reduced until it will
pass completely through a 120-mcsh sieve
A microcrystallinc powder is preferred where
possible In general, the partially melted sup-
pository base should be used as the leviga-
Fio 88 Suppository mold of transverse
partition design, open (Witepsol, Che
mischc Werke Witten, 1961)
Uon agent, however, m formulas containing
more than JO per cent of powder a liquid
Icvigation agent is added to about one half
the weight of the powder A vegetable oil is
preferred for use with the fatty bases and one
of the liquid components (glycerin, poly-
ethylene glycol 400 or water) is chosen for
the water soluble bases
Castor oil is used to aid the mcomration
of extracts, particularly when alcohol is used
to soften the hardened pilular extract Usu-
ally the alcohol will have evaporated almost
completely before the softened material is
finally incorporated, otherwise there will be
(a) the possibility of irritation, (b) migra-
tion to the surface of the alcohol soluble con-
stituents on storage, (c) change in medica-
ment release because of solvent effect of
alcohol or nugration of drug
For the incorporation of large amounts of
powder into suppositories the same rules
should be followed m the choice of a Icviga-
tion agent as arc followed m the preparation
of ointments An additional requirement is
that the Icvigation agent be nonirritating to
the mucous surface of the cavity
Care should be taken m tlic fusion process
that the suspended powders continue to be
dispersed uniformly throughout the supposi-
tory mass until it has congealed The mass is
healed until it has just reached a creamy,
pourable consistency and is stirred while
being poured When properly handled, con
gealing takes place relatively quickly, thus
preventing separation Lehman’’ reported
that the addition of aluminum stearate to the
fatty bases aided suspension of the powders
dunng the criucal phase by mcrcasmg the
viscosity of the mcltra base
Special Dispensing and Compounding Procedures for Suppos for es 239
Fig 89 Suppos tory mold ng using plost c shells {Top lejt) Placing the mat ready for
molding [Top ng! t) The filled shells ready for mounting on stems {Bottom lejt) The
molded and capped suppositones {Bottom right) The user removing the suppository from
Its shell (Chemical and Pharmaceut cal Industry Co Inc )
Lubncatiod The suppository mold_^en ceotration of soluble drug is mixed with the
erally do es not require lubn cati oa if the sur base Thcobroma oil is particularly sensitive,
face iTclcan and p olished T he mass sh ould because of the low melting poI)Tnorphic
have sufficient contraction to free the molded forms which arc possible and its high molal
form on cogliog and time_shoul d be al/oi sed freezing point depression The problem may
for the complete con traction [ Should diffi-Q be solved without change in the formula by
culty indicating requirement of XlQbri^l^ requiring that the finished suppository be
occur the'choice^hbuld’ be made of a light stored at suffic enlly low lefngerator tem
min eral oIFcoating fo r the watecjsoluble^^ perature to mamtain the solid form until use
hnseit fnuy hasg <>,jwa^tcr v^icb Mil con^^The use of bceswax or spermaceti in amounts
deSJe from the atmosphere _as a very thin sufficient to raise the melting temperature is
film on tKe~cbilled~moIiris' usu^y the be st not without difficulty as the method of treat
lubricant Aqueous soap solutions, may_bc .jment of the drug theobroma oil-wax mix
applied as a light film of a very dilute solution *'^turc prior to and dunng congealing will
Dusting Powders Suppositones properly determine the melung temperature of the fin
formulated and properly made need no dust ,shed suppository Also there is the possi
mg powders Should extemporaneously com (jdjty of a change in the mcltmg temperature
pounded suppositories require a powder it on storage as theobroma oil reverts to a
is suggested that starch be used and then in lugijej. melting polymorph Example
a rmnunum amount Excess powder par
ticularly of a type which is not easily wetted ^
may mtciferc with release of the mcdicaiion Hydrate 500 mg
Lowered MtlUng Temperature A charao-
tcnstjc lowering of solidification and melting
temperatures occurs when a significant con In this prcscnption 500 mg of wax per sup
240 Suppositones
posilory IS chosen as the means to raise the
melting temperature and is melted over a
water bath The chloral hjdratc is added
without further addition of heat Before con-
gealing takes place, grated cocoa butter is
added (1 Gm per suppository) The mass
IS mixed and warmed carefully to aid ui for-
mation of a uniform dispersion and then
poured into molds The suppositories are
allowed to harden thoroughly m the chilled
mold and then are trimmed and removed.
The weight is determined to find if further
addition of drug or base is required to adjust
the dose If required, grated cocoa butter or
drug IS added to the melted drug base and
then warmed and mixed together uni3 pour-
able, and recast mto the molds The finished
suppositoncs should be allowed to remam
under refrigeration or in a cool place for a
few days and then should be tested for melt-
mg at bady temperature
C7sc of Plastic Afolds. A few years ago
plastic molds were introduced as a replace-
ment of the traditional metal molds The
plastic mold does not have the mechanical
strength, loses polish more easily so that
sticking IS more of a problem and does not
conduct heat as readily as the metal mold
These disadvantages have been set aside
partly by the use of thm shells of plastic m
two pieces that allow molding of the sup-
pository and dispensing it in the mold which
senes as its package The patient may cosily
remove the suppository and discard the shell
at the time of use Many commercial supposi-
tory formulas may be conveniently packaged
in this way with economic efiicicney Its use
on a small scale will depend on the availabil-
ity of a smaller molding tray Currently, the
molding tray holds 288 of the plasuc shells
(Fig 89)
REFERENCES
1 AUawala, N A, and Rcigelman, S J
Am. Phann. Assoc, (Sci ) 42 267, 19S4
2. Bochcnuhl, and Middcndorf, U S PaL
2,149005, 1937
3 Bucher, K- Helv physiol phannacoL
actad 821,1948
4 Cacchilo, A F , and Hassler, W H J
Am Pharra AsWe (Set ) 43 683, 1954
5 Collins, A P , Hohman, J R , and Zopf,
L. a Am, Prof Pharm 23 231, 1957
6 Deutsches Amzcibuch VI, 3rd suppi ,
1959
7 Eckert, V , and Muhleman, H Pharm.
acta helv 33 649, 1958
8 Guida, A F An In Vitro Method for
the Study of Theophylline Release from
Suppository Bases, Thesis Univ Kansas,
1952
9 Hcnnig W Ueber die Reklale ResorpLon
von Medicamentcn, Zunch, Juris Verlag,
1959
10 Hopp G En Sammenlikncnde under-
sokeke over gninnmasscr og fremsuUings
metoder for suppositorrer, Oslo, 1961
11 Kremers, E., and Urdang, G History of
Pharmacy, ed, 2 Philadelphia, Lippiocott,
1951
12. Lehman, H Schwea Apoth ZciL 97 555,
1959
13 Meara. M L. J Cbero Soc 1949, 2154
14 Oesch, P Ueber die HcrstcUuog und
PrufuDg von Suppositonen, Zurich, Ernst
Long 1944
15 Pennati, L., and Steiger Tnppi, K Phann
acta helv 33 663,1958
16 Rcigclman S , and Crowell, W J J Am.
Pharm Assoc (Sei) 47 115, 123, 127,
1959
17 Robertson, J S J Phann. Sci SO 21,
1961
18 Schankcr L. S J Pharmacol Exper
Thcr 126 283, 1959
19 Setnikar 1 , and FanteUi, S J Pharm
Scl5/ 566, 1962
20 Smith, A Tcchnjc of Medication, Phila
deJphia, Dppmeott, 1948
21 ^jcrandio, G J , and Hassler, W H J
Am. Pharm Assoc. (Pract ) 14 26 1953
22. Tardos L., Weuman, L. J , and EIlo,
Pharmazie 74 526 1960
23 Tardos, L., Elio, Magda, and Jc^bagyi
Acta Phann. Hung 29 22 1959
24 Taylor. A B Am / Pharm 24 211.
1852.
25 Ticc, L. F, and Abrams, R. E Am
Prof Pharm 18 327, 1952
26 United Stales Pharmacopcu XVI, Mack,
1960
C/japfer 8
Aerosols
John J Scjorra, Ph D.*
INTRODUCTION
Tlie application of the principles of aero
sols or pressurized packaging to medicinal
and pharmaceutical products is of relatively
recent occurrence X^ile it is true that sev-
eral spray-on antiseptics, burn preparations
and local anesthetics were available during
the early years of the aerosol industry, it is
only during the past 5 or 10 )ears that sen
ous mterest has been given to die formulation
of suitable phannaceutical and medicinal
aerosols In 1962, over 31 million units of
medicmal and pharmaceutical aerosol prod
ucts were produced in the United States This
represented an mcrease of 72 2 per cent from
the 1961 figure (over 18 million), an m-
crease of 181 per cent from 1960 figure (over
1 1 million) and a 300 0 per cent mcrease
from the 1959 figure (over 10 million) When
It IS noted that less than 1 mdhon units of
these products were produced m 1952, the
newness of the development and the in-
creased mterest m this area is quickly ascer-
tained. Figure 90 traces the growth of me-
dicmal and pharmaceutical aerosols m the
Umted States from 1953 to 1962
Pressurized containers for pharmaceutical
products actually were used for many years
on a small scale and for special purposes
Many will recall the physicians’ use of ethyl
chlonde for mmor surgery-® This product
consisted of eth}l chlonde (acting as boih
propellant and active ingredient) packaged
in a glass ampul fitted with a valve When
the ethyl chlonde ampul was held m the
warmth of the hands, Ae vapor pressure of
* Professor of PbannaceuUcal Cheimsuy, St.
Johns University College of Pharmacy
the ethyl chlonde increased After the valve
was opened, the liquid ethyl chlonde escaped
Since the boilmg pomt of ethyl chlonde is
12 3® C, It re\erted quickly to the vapor
state This caused a freezmg of the skm and
tissues with resultant local anesthetic effect
A host of aerosol products have evolved
which are of interest to the pharmacist from
both a commercial and a scientific viewpomt
Ever smee the first aerosol products were
developed, the community pharmacy has
been a major outlet for their distribution
These products include insecticides, hair lac-
quen, room deodorants, shave creams, per-
fumes and colognes, as well as some of the
more specific pharmaceutical and medicmal
aerosols such as the bum preparations, the
local anesthetics, the steroids, the first aid
products, the antiasthmatic and migrame
preparations, the dental creams, etc which
are part of the daily annamentanum of the
professional pharmacist The products have
been formulated utihzmg different aerosol
systems— each s)stem designed to serve a
specific puqx>sc This newer method for the
(hspensing of medicmal and pharmaceutical
pn^ucts has many advantages over the more
conventional methods and, m some instances,
has made popular products that cannot be
dispensed or applied efficiently by any other
method — for example, hair lacquer
From a scientific viewpomt, aerosols are
important to the professional pharmacist
smee they have become another dosage form
Smcc aerosols have invaded the domain of
the pharmaceutical field and arc sold to such
a large extent by the pharmacist both over-
the-counter and on prcscriptiou, it is the re-
sponsibility of the professional pharmacist
241
242 Aerosols
Fig 90 Growth of aerosol drugs and
pharmaceuticals
to equip himself with as much knowledge as
possible m regard to aerosol products “ In
this way he can render another professional
service to both patient and physiaan. A
knowledge of aerosol formulation and com*
ponents IS essential in order to discuss these
products inteUigently As the technology in-
creases m this field the pharmacist may well
find himself compoundmg a number of
aerosol presenpuons extemporaneously
DEFINITIONS
The term aerosol is defined as a system
consisting of a suspension of fine solid or
liquid particles m air or gas As such, smoke,
fog. dust or moisture suspended m the atmos-
phere, etc , can be classified as aerosols
While this IS generally accepted as the classi-
cal definition of the term, a more recent defi-
nition includes as aerosols those products
which depend on the power of a liquefied or
a compressed gas to expel the contents from
the container This is slightly different from
the definition advanced by the Chemical
Specialties Manufacturers Association which
includes only those products utilizing a
liquefied gas propellant ^ Terms such as
“pressure pack,” “pressurized packaging,”
‘pressurized product” etc arc also used to
desenbe this type of product It is m the
light of the newer definiuon that the term
aerosol is used m this chapter
Ongmally, the term aerosol referred to
liquid or solid particles of a specific size
range, but this concept is falling into disuse
However, one current system for the classi-
fication of aerosol products is based on par-
ticle size for example, space sprays dispense
the active ingredients as a finely divided spray
with the particles no larger than 50 microns
m diameter, while those sprajs having par-
ticles considerably larger are classified as
surface coaling sprays The latter generally
produce a wet or a coarse spray and are used
to coat a surface with a residud film Finally,
the aerated foam system completes this
classification of aerosol products This sys-
tem IS used when a foam, such as is found m
shaving creams, rather than a spray, is de-
sired The charactenstics of the foam depend
on the nature of the formulation and will be
described in greater detail m a later portion
of this chapter
All of Uie existing aerosol products can
be encompassed within the above classifica-
tion Medicinal and pharmaceutical aerosols
arc included m the general definitions How-
History 243
ever, the pnociples and the considerations
involved m the formulation of aerosol prod-
ucts used for a therapeutic response are quite
different from those reeardmg other aerosols
and, in addition, differences exist between
those aerosols mtended for internal adminis-
tration and those for topical admmistration
Therefore, it is advantageous from the view-
point of discussion as well as formulation to
disUnguish between these types of aerosol
products
hlcdicmal aerosols may be defined as those
aerosol products contaimng therapeutically
aaive ingredients dissolved or suspended in
a propellant or a mixture of a solvent and
a propellant and intended for administration
as fine solid particles or liquid tmsts via the
respiratory system or the nasal passages
They are mtended for local acuon in the
nasal areas, the throat and the lungs as well
as for prompt systemic effect when ab-
sorbed from ^e lungs into the bloodstream
(inhalation or aerosol therapy) The particle
size must be considerably below 50 miaons
and, m most instances, should be between
0 5 and 1 0 microns for maximum therapeutic
activity
Pharmaceutical aerosols may be defined
as aerosol products contammg therapeutically
acuve ingredients dissolved, suspended or
emulsified m a propellant or a mixture of
solvent and propellant and mtended for
topical admmistration or for administration
mto one of the body caviUcs such as the ear,
the rectum and the vagina Ophthalmic prep-
arations may also be included m this dcGni
tion when they are developed
In this chapter, pharmaccuucal and me-
dicinal aerosols will be discussed in the light
of the precedmg definitions, but several other
definitions have been advanced Kanig®^ de-
fines both medicmal and pharmaceutical
aerosols as ' those which are admiiustcred
mtcmally or externally and which have a
therapeutic effect in the cure or alleviation
of any human or animal disease or condi-
tion ”
HISTORY
Aerosol products were first mtroduced in
the United States about 1942** when the
well Lnown aerosol insecticide was developed
as a result of the mvestigations of Goodhue-*
and Sullivan"* of the United States Depart-
ment of Agriculture The msecticidal aerosols
produced a fine spray, and particles of m-
secticide remamed suspended m air for a
relatively long penod of time, makmg them
extreo^ly effective agamst insects and house-
hold pests These preparations were used by
members of the Armed Forces throughout
the world, especially m malaria infested
jungles and swamps, and them effectiveness
has been well established They were gen-
erally m high pressure cjlmders, since the
propellant available at the time was dichloro-
difluoromethane which has a vapor pressure
of 70 pounds per square mch gauge (psig)
at 70" F • Interstate Commerce Commission
regulations necessitated a heavy, bulky steel
contamcr for the shipment of ^csc products
m interstate commerce Figure 91 illustrates
a typical product of this kmd Followmg
World War II, newer propellants, valves and
coolamcrs were developed so that a spray
possessmg the proper particle size could be
produced using a pressure of 35 to 40 psig
In 1947, an amendment to the Interstate
*The term psig represents the uncorrected gauge
pressure and is to be distinguished from psia which
represents pounds per square inch absolute — that is,
corrected to include atmospbenc pressure (14 7
psig)
Flo 91 Original aerosol “bug
temb **
244 Aerosols
Commerce Comnmsion regulations per-
mitted pressures of 40 psig at 70° F in ihin-
wallcd contamers The lo'Acr pressure made
possible the use of a ‘ beer-can” t)pe of con-
tainer (Fig 92) which could be mass-pro-
duced at a considerably loucr pnee ^an
the heavy-walled contamers
Alummum and stainless steel containers
were developed for use with medicmal and
pharmaceutical products as well as for sev-
eral perfumes and colognes ** The develop-
ment of the low-pressure and the ultra low-
pressure ( I S 25 psig) aerosols made possible
the use of glass and plastic-coated glass con-
tainers Plastic contamers have been de-
veloped and arc findmg use for certain per-
fume and cologne aerosols
With the development of the standard 1-
inch openmg for tm plate contamers, vanous
%'ahes were designed to dispense the product
m many different ways, such as a fine stream,
a fine mist a coarse spray, a foam etc An
important milcstoae-^sscnual for medicinal
Fio 92 Beer can" type aerosol
container (Coniincntal Can Com
pany)
aerosols — was the development of a metered-
valvc FoUowmg this, many other metered
valves were developed utilmng different prin-
ciples so that today metered valves are com-
mercially available for dispensmg quantities
of concentrate from as low as SO mg to as
much as 1 ounce
While the work of Goodhue and Sullivan
formed the basts for the modern-day aerosol,
the dispensing of products from a pressurized
container antedates many of the current
aerosol products In fact, the first commercial
aerosols were pharmaceutical propnetanes **
The vainous products covered by Gebaucr
m his basic patents were pressurized prod-
ucts “ Ethyl chloride, tannic acid and
surgical soap were marketed in this manner
Several of these products are shown m Figure
93 Several antiseptic solutions were de-
veloped utilizmg carbon dioxide as the pro-
pellant*® The atomizer has been on the
medical scene for about one hundred years
and represents an early development for the
administration of substances in aerosol
form ®* In fact, the atomizer was used to a
great extent to aerosolize hair lacquers pnor
to the use of liquefied gases for this pur^se
While many of these atomizers and similar
devices were cumbersome and bulky to use,
they were the only devices available for this
purpose Chapter 2 indicates the use of
atomizers, nebulizers, vaporizers etc
While the method of inhalation or aerosol
thempy IS not new, formulation and develop-
ment of a convenient, effective self spraying
unit IS the result of recent endeavors The
ancients recorded the efficacy of the vapors
from bummg leaves and herbs, within the
past 30 )cars, the smoke from burning
stramonium leaves has been used m the
treatment of asthma The burning of sulfur
candles to disinfect the air and the spraymg
of operating rooms with germicidal materials
arc well known and effective means for
fumigation and sterilization A patient par-
taking of the beneficial effects of salt air at
a beach may be ulilizmg aerosol therapy un-
knowingly when the mmute salt particles m
the air produced by the atomization forces of
the breakers are mhalcd
The first medicmal aerosol product ap-
peared m the Umted States m 1955 This
Pharmaceutical and Med cinal Aerosols
245
product — ^Medi Haler Epi (Riker Labora
tones) — was intended for local action in
the lungs and was effective in relieving the
symptoms of asthmatic attacks Following
this other products were developed for use
as antiasthmatics treatment of the symptoms
of angina pectons nasal vasoconstnctois and
treatment of migraine headaches
Pharmaceutical aerosols were first de
veloped m the early 1950 s and mcluded
local anesthetics antiseptics spray-on band
ages topical creams and ointments bum
preparations and toward the end of the
1950 s several vitamm preparations
PHARMACEUTICAL AND
MEDICINAL AEROSOLS
Before considcnng other aspects of phar
maceutical and medicmal aerosols an ex
ammation of the advantages of aerosol
products may be desirable
General Advantages
1 The product is more convenient to
use since the package is a compact unit and
the product can be appbed or admmistered
easily and quickly
2 Smee the medication is sealed m a
pressurized container there is no danger of
contammation of the product with foreign
materials and at the same tune the con
tents can be protected from the deletenous
effects of both air and moisture
3 If the product is packaged under
sterile conditions sterility is maintained
throughtout the life of the product
4 Through use of metered valves accu
rate dosage can be obtamed
Advantages of Pharmaceutical Aerosol
Preparations
1 The irritation produced by the me
chanical application of a medicmal over an
abraded area of the skm is reduced and
sometimes elimmated by a spray-on aerosol
2 Fmely powdered drugs such as anti
biotics can be convemenUy administered
from this type of container
3 There is no danger of contammauon of
the unused portion of the aerosol medica
ment from an infected wound as is possible
with conventional packages
4 Smee the medicinal is applied directly
from the container to the affected area of the
Fig 93 Early pressurized products
skin there is no waste or messiness such as
accompanies the use of an applicator or a
cotton swab
5 Liquefied gas aerosols dry rapidly due
to the cooling effect of the vaponzation of the
propellant, which may be desirable m certam
cases
6 The medication can be applied m an
extremely ihm layer duectly over the affected
area resulung m faster absorption and more
efficient utilization of a given amount of
medication
Advantages of Medicinal Aerosols (In*
halation Therapy )
1 Some medicmals formerly given as an
injection can be admmistered by inhalation
thereby makmg possible self medication at
home by the patient m place of admmistra
tion by medically tramed personnel m the
office or hospital
2 The dangers of givmg medicmals by
injection (trauma embolism stenic ab-
scesses etc ) are avoided smee inhalation
therapy will often replace an mjectable
product
3 The use of medicmals by inhalation
docs away with the necessity for elaborate
sterile preparations requued for parenteral
adnunistratioo
4 Response to drugs administered by m
halation is prompt foster m onset of activity
as compared with response to drugs given
orally and with most drugs approaches m
travenous therapy m rapidity of action
246 Aerosols
OPEJIATES BT
PKESStKO OOIN
Fig 94 Cross scciion of typical space or
surface spray
5 Since ihc drugs arc absorbed directly
into the blood stream via the lungs there
IS no decomposition or loss of drug in the
gastromlcstmal tract such as occurs when the
drug IS admmistcrcd oraffy
MODE OF OPERATION OF
AEROSOLS
Aerosol systems may be classified as fo)
lous
1 Liquefied gas systems
A Two-phase system
a Space spray
b Surfaee spray
c Dispersion or suspension sys
tern
B Three phase system
a Two-layer
b Foam system
2 Compressed gas systems
A Solid stream dispensmg
a Insoluble inert gases
B Foam dispensmg
a Soluble mert gases
C Spray dispensing
a Soluble inert gases
b Insoluble inert gases
Liquefied Gas Systems
When an aerosol preparation stands at
room temperature m a closed contamer, some
of the propellant will change from a liquid to
a gas and fill the empty space m the con
tamer An equilibrium is soon reached be-
tween the number of molecules gomg from
liquid to vapor and from vapor to liquid
Equilibrium is established when the pressure
wiihm the container becomes equal to the
vapor pressure of the propellant This vapor
pressure is exerted equally m all directions
and is independent of the quantity present
When the valve of the contamer is opened,
the pressure forces some of the liquid up the
dip tube and through the valve When the
liquid material comes into contact with the
warm air at aimosphenc pressure, the pro-
pellant portion of the formulation instantly
changes to a gas and, m so doing, dispenses
the active ingredients as a fine spray The
volume of head space wjihm the container is
mcrcoscd as the product is discharged This
causes a temporary drop in presstre as a
result of the expansion of the gas m the
vapor phase Some of the hquid propellant
now changes to the vapor phase, thus,
quickly rcstonng equilibrium and original
pressure (This is a significant difference
from compressed gas aerosols )
Two-Phase System. Space sprays and sur-
face sprays function as indicated m the pre-
ceding paragraph Tlic two types of spray
differ m regard to pressure within the eon-
tamer the space spray has a pressure of
to to 40 psig, producing a fine mist so that
the particles remain suspended in air for at
least 40 to 60 minutes, the surface spray is
slightly lower in pressure and is used to coat
a surface with active mgrcdicnts rather than
suspendmg particles m air Residual insecti-
cides, moihproofcrs, paints and pamt re-
movers make up some of the surface sprays
Figure 94 shows a typical two phase system
Mode of Operation of Aerosols 247
applicable for use as cither a space or a sur-
face spray
The two phase system is also used for
both medianal and pharmaceutical aerosols
The active ingredients are dissolved m the
propellant or a mixture of propellant and
solvent ^Vhea the valve of the aerosol is
depressed, active mgredicnts and propellant,
or propellant and solvent are released Pro-
pellant and solvent vaporize quickly, leavuig
behmd the finely subdivided active ingredi-
ents This system has been used to great
advantage for both medicmal and pharma-
ceutical aerosols However, several problems
m formulation become immediately apparent
For the most part, the therapeutically active
ingredients are not directly soluble m the
propellants and must be (^solved through
use of a suitable cosolvent The solvents avad-
able for this purpose are lumted to those
sbowmg very little, if any, imtation and
toxicity when used topically or by inhala-
tion Lack of adequate data on toxicity for
many solvents further complicates the formu-
lation of such products Ethyl alcohol,
mmeral oil, glycerin, propylene ^)col, poly-
ethylene and polypropylene glycol, acetone
and ethyl acetate are a few of the solvents
that have been used When one considen
soUents for inhalation, the list is considerably
narrowed
Dispersion or Suspension System In-
soluble materials can be suspended m a
liquefied gas propellant through the use of
suitable dispcrsmg agents Several aerosols
contaming insoluble matenals have been de-
veloped and consist pnmanly of talcum, dis-
persmg agents such as isopropyl mynstate,
and propellant Pamt aerosols are included
m this category Anubiotic and steroid
aerosols are further examples of this type
In several medicinal aerosols containing
epmephnne and ergotamme the therapeu-
tically active ingredients are suspended m the
propellant In use, the propellant evaporates,
leaving behind the finely dispersed active in-
gredients This system is a useful method
for the application of antibioucs and other
medicinal agents
Three-Phase System. This system is ebar-
actenzed by the presence of a greater quan-
tity of water than is found in a two-phase
system Since water is not miscible with the
propellants that are generally used, separa-
tion will occur unless an emulsion is formed
Dependmg on the type of formulauon de-
sired, one of the two following systems may
be employed
Two Layer System The active ingre-
dients are dissolved m water or an aqueous
base, and, when propellant is added, two
immiscible layers are formed Depending on
the density of the propellant, the propellant
cither will float on top of the aqueous solu-
tion or wU fall to the bottom of the con-
tainer The propellant is one phase, the
second phase consists of the aqueous solu-
tion, finally, some of the propellant vaporizes
and fills the head space to make up the third
phase The propellant vaponzes due to the
decrease m pressure as the contents of this
three-phase aerosol dimmish, and the gas
passes through the aqueous solution (if the
propellant is the heavier layer) and restores
248 Aeroiols
Fw 96 Foam typo aerosol Fic 97 Cempreased gas aerosol
the pressure m the head space Ooly a small
quantity of propellant is used in aerosols of
this type, and only aqueous solution is dis-
peosca The absence of propellant from the
dispensed solution necessitates the use of a
specially designed nozzle to produce the
proper spray Figure 95 shows such an
aerosol
Sc^cral products utilize a hydrocarbon
such as isobutanc or propane as the pro-
pellant The hydrocarbons ore used in the
same way as arc the fluorocarbons for this
purpose, except that the hydrocarbon is
lighter than water and floats on top of the
aqueous layer Several household cleaners
and mothproofers are examples of three-
phase aerosols
This system has not been utilized to date
for pharmaceutical and medicinal aerosols
It should be useful for the dispcnsmg of
various antiseptic solutions Through use of
a suitable actuator and baffle (similar to a
ncbuhzcr) the desired type of spray may be
obtained.
Foam SysTE^t Foam aerosols operate on
essentially the same prmcipic as the two-
phase system except that the propellant is
partially emulsified with the active ingre-
dients \Vhen the valve is depressed, the
emulsion is forced through the nozzle and,
m the presence of warm air and at atmos-
pheric pressure, the entrapped propellant
changes to a gas and whips the emulsion into
a foam Foam products operate at about 35
to 40 psig at 70® F and contain about 6 to
10 per cent of propellant as compared with
about 80 to 90 per cent of propellant for
spray products Figure 96 shows a foam
type aerosol When the container is supplied
with a dip lube (as shown in Fig 96), the
ojalamcc is held upnght during use Some
products do not contain a dip tube, and,
therefore, the directions specify that the con-
tainer be inverted pnor to use It is important
that the directions be followed, otherwise,
the propellant may escape without dispensing
the active ingrcicnts Another important
consideration is that these products must be
Mode of Operohon of Aerosols 249
Table 36 Petrolatum as a Compressed Gas Aerosol*
CoMPosiTiov OF Base
Liquid
Petrolatum Petrolatum
% w/w % w/w
Physical
Appearance
Dispensing
Characteristics
0
100
Limpid oily liquid
A
10
90
Limpid ody liquid
A
20
80
Limpid oily liquid
A
30
70
Viscous ody liquid
A
40
60
Viscous ody liquid
A
50
50
JellyliLe semisolid
B
60
40
JeUyliLe scmisolid
C
70
30
Jellylike semisolid
D
80
20
Viscous semisolid
E
90
10
Viscous semisolid
E
100
0
Viscous semisolid
F
• Nitrogen at 90 psig
A — Too limpid, does not adhere to skin surface
B -x Flowed evenly, may be a little too funpid. docs not adhere to skjo surface
C — - Produced a pr^uct having most of the desired cbaractenstics
D — Could be dispensed, may be too viscous.
B— Could be dispensed, too viscous to be spread over sbn surface
P ~ Could not be dispensed
From Sciarra, J J , Turney. P J , and Fecly, W J The formulation of topical pharmaceuticals m
aerosol packages. Drug Standards 2S 20. 1960
shaken before use As these are eraulsioo
t)pe products, there is a certain amount of
separation of active ingredients and pro-
pellant so that shaking is required to pro-
duce a homogeneous mixture This is another
significant difference from most of the com-
pressed gas aerosols which specify that the
container is not to be shaken and is to be
held upnght during use Shave creams and
shampoos are examples of foam type aero-
sols While It IS highly unlikely that this sys-
tem will be useful for medicinal aerosols, it
has been used for the formulation of pharma-
ceutical aerosols The product is dispensed
as a foam which can then be applied to the
affected area In this manner the medicinal
agent can be applied either to a limited area
or to a larger area with very little, if any,
imtauon due to application of the medicinal
A recent advance in this area is the develop-
ment of the “quick-breaking” foam The
product IS dispensed as a foam, but, m con-
tact with skin areas, the foam quickly col-
lapses, Icavmg only the solution of medicinal
agent This makes possible the apphcation of
mcdicmals to wounded or abraded areas
without the necessity of tubbing to disperse
the medicinal This is highly desirable when
applying raedicinals to such areas
Compressed Gas Aerosols
Depending on the nature of the formula-
tion and the type of valve used, a compressed
gas can be used to dispense the product as a
solid stream, a fine mist or a foam
In aerosol products of this type an inert
gas such as mtrogen, carbon dioxide, nitrous
oxide etc is used as the propellant (Fig 97 )
As the name indicates, the gas is compressed
in the container, and it is the expansion of
the compressed gas which provides the push
or the force necessary to expel the contents
from the container This is essentially the
same pnnciple as the liquefied gas aerosol
except that there is little or no reservoir of
gas, so that as the contents of the container
arc expelled the volume of the gas will in-
crease causing a drop m pressure according
to Boyle’s Law.
P = k“ where p = pressure, V = volume of gas
Solid Stream Dlspcnsiag. Nitrogen is used
as the propellant for this type of product
2i0 Aerosols
Table 37 Polyethylene Glycol as a Compressed Gas Aerosol*
Composition op Base
PEG 4 000 PEG 400
^0 W/W % W/W
Physical
Appearance
Dispensing
ClURACTERISnCS
0
100
Limpid liquid
A
5
95
Viscous liquid
C
10
90
Very viscous liquid
C
20
80
Jellylike semisolid
D
30
70
Viscous semisolid
D
40
60
Very viscous semisolid
F
50
50
Very viscous semisolid
F
* Nilrogcn at 90 psig
A — TooUmpid does sot adhere la sLin surface
C — Produced a product having most of the desired charactcnslics.
D — Could be dispensed, may be too viscous
F — Could not be dispensed
From Sciama J J , Tinney, F 1 . and Feely, W J Drug Standards 2S 20
Nitrogen is essentially insoluble m the mix-
ture of active ingredients so that only the
concentrate is dispensed and none of the
gas This makes possible the dispensing of a
product m its onginal form and is suitra for
Fio 98 Sclf-
agilaling aerosol
product (Con-
tinental Enter-
prises, Inc.)
the (lispcnsmg of tooth pastes, hair dressings,
ointments and creams, cosmetic creams,
cough syrups, vitamins, foods, and other
E roducls It IS because of the lack of solu<
ility and the fact that the product is to be
dispensed as a stream and not as a spray that
one is cautioned not to shake a compressed
gas aerosol containing nitrogen prior to use
The cooccDtraie is generally scmtsolid m
nature and the dispensing characteristics arc
largely dependent on the viscosity of the
product and the pressure within the eon-
tamer ** Since there is no liquefied gas pres-
ent, compressed gas aerosols operate at a
substantially higher initial pressure of 90 to
100 psig at 70® F nils higher initial pres-
sure IS necessary to ensure adequate pressure
for tile d/speasing of most of foe conieets
from the container The amount of product
rctamed m the unit after exhaustion of the
pressure vanes with the viscosity of the
product and loss of pressure due to seepage
of gas during storage
Some dental creams and hair preparations
utilize this aerosol system
In order to detemune the dispensing char-
acteristics of several commonly used oint-
ment bases IS hen formulated as a compressed
gas aerosol, Sciarra, Tinney and Feely'* used
a petrolatum base and a polyethylene glycol
base These were packed into aerosol con-
tainers utilizing nitrogen as the propellant.
Tables 36 and 37 show the results of their
investigation
Several problems arise during the formula-
Mode of Operation of Aerosols 251
tion of compressed gas aerosols because all
of the product cannot be dispensed from the
container, and, in the case of extremely vis-
cous materials, the product does not Sow
rcathly, resulting in cavitation and subse-
quent loss of gaseous propellant. This has
been partially overcome through use of a
piston type container in which the gas pushes
against a piston which, in turn, exerts a pres-
sure against the product.^ This ensures a
more uniform dispensing of the product and
is applicable to semisolid pharmaceutical
preparations. Other similar devdccs make use
of a thin plastic or polyethylene bag to hold
the concentrate product.*®
Foam Dispensing. This system is s imil ar to
the liquefied-gas foam system except that
nitrous oxide and carbon dioxide arc used
as the propellants. Recently, a mixture of a
liquefi^ gas (octafluorocyclobutane) and
nitrous oxide has been introduced for use in
whipped creams and toppings. These gases
are soluble in the product concentrate (which
is generally an emulsified product) and,
when the aerosol is dispensed, some of the
soluble compressed gas is emitted with the
concentrate. This will cause a w'hipping of
the cream. In this type, shaking of the con-
tainer prior to use Is desired in order to mix
some of the gas with the active ingredients.
Fio. 99. Addition of propellant by the cold Ming process.
252
Aerosols
Spray Dtspcnsmg This system is similar
to a tuo-phasc s)stcm except for the pro*
pcllant A compressed gas such as nitrogen,
carbon dioxide or nitrous oxide is used Smee
the compressed gases do not possess the dis-
persing po\^er of the liquefied gases, a me-
chanical breakup actuator is used and a ixct
spray can be produced Nitrogen is used to
(hspense an aqueous solution of an lodme
complex, nitrous oxide has been used to dis
pense a barbecue sauce, while carbon dioxide
IS used to dispense a de icer spray Webster**
has investigated the use of some of the solu
blc compressed gases as propellants for
products requiring a fine spray The major
advantage of this type of system is that the
propellant has greater compatibility with
aqueous liquids
A recently developed compressed gas
aerosol system is unique in that it makes use
of three variables, namely the viscosity of
the product, the orifice of the valve and the
pressure within the container, to dispense the
product as a fast moving jet ’ stream which
becomes self agitating if it is directed uito
milk or water*® In this process, a soluble
compressed gas is used to dispense the prod
net as an aerated foam mto a hquid diluent
Monufacture of Aerosol Products
253
As the foam comes mto contact Vrith the
dQuent, the gases trapped withm the foam
expand, resultmg in a complete mixture of
the concentrate with the diluent Whde die
soluble compressed gases have greater dis-
persmg power, mtrogen also can be used
advantageously The pnnciple has been ap-
plied to several flavored syrups (chocolate,
strawberry etc ) with success At the present
time, the system is used pnncipally m the
dispensing of food and beverage concen-
trates,®^ but It may be used for dispcnsmg
many pharmaceutical syrups, elixirs and
other liquid products Figure 9S shows the
dispensmg of such a product
MANUFACTURE OF AEROSOL
PRODUCTS
A propellant compound can be hquefied
either by lowering the temperature below its
boiling pomt or by an increase m pressure
When the propellant is kept below its boDing
pomt or at a pressure above its vapor pres-
sure, the propellant will be m the hqmd
state This is essentially the basis for the two
methods used to fill liquefied gas aerosol
products
Laboratory Procedures
Cold Process. In the cold process, the
active mgredients are chilled and weighed
into an open contamer Then the cold pro-
pellant IS metered mto the contamer and
the container is sealed by cnmping the valve
m place This unit is then heated m a water
ba^ to 130° F to test for leaks and to test
the strength of the contamer Figure 99 shows
the addition of the propellant component to
the concentrate and Hgure 100 illustrates
the cnmpmg of the valve onto the aerosol
contamer A schematic diagram of the cold
fillmg apparatus is shown m Figure 101
This method is fast but is not generally
CAUTION: Outlet valve on cylinder and valve on niins line should never both be closed at the same time,
thereby Uapp ng Uqu d wh ch may expand and rupture I ne- One or both valves should always be open.
NOTE Aerosol canUmtr to be TI ed u cooled before fa ng by Hnmerxng n Finely ground «ol d urbon dioude.
Fig 101 Laboratoiy cold fillmg of aerosob (E. I duPoot dc Nemours and Co , loc )
254 Aerosols
suited for aqueous and emulsion t)’pc prod cnmpcd into place the trapped air is cvacu
ucts since the concentrate will freeze and ated from the cootamer via a vacuum pump
solidify at these low temperatures ( — 40“ or evacuated at the same time that the valve
F ) IS inserted through use of a combmauon
Pressure Process This process can be used crimper and vacuumizing unit The propellant
for aerosol products of all types The con is added through the valve utilizing the vapor
centrate is prepared in the usual manner and pressure of the propellant to force it through
placed into the aerosol contamcr at room the valve This is shown m Figure 103, a
temperature (Fig 102) After the valve is dtngram of the apparatus is given m Figure
Fio 102 Add I on of product to aerosol container (Allied Chemical Corp
General Chemical Div }
Manufacture of Aerosol Products 255
104 Since a relatively large amount of
propellant must be forced through a small
valve openmg, newer techniques utilize the
pressure of nitrogen or another compressed
gas on the propellant to force the propellant
through the valve openings In this way
speeds comparable with that of the cold filling
process are attained
The differences between these two methods
have been summarized by Herzka and Pick-
thall”
soluble compressed gases, the contents must
be shaken during the gassing operation,
either mechanically or by hand, to ensure
adequate solution of the gas m the concen-
trate
Large-Scale Production of
Aerosol Products
Since aerosol technics are quite different
from the usual pharmaceutical procedures, it
may be advantageous to discuss the procc-
Cold Process
1 Not suitable for small to medium produc
tion runs at moderate speeds
2 Propellant losses are likely to occur
3 Unsuitable for inflammable propellants
4 The moisture content of the pack is likely
to increase during filling
5 Heat has first of all to be removed from
the product and the propellant and then re-
placed in order to bring the temperature of the
pack to 130* F
6 The product must have reasonable vis-
cosities at low temperature and must be un-
affected by refngerauon Therefore, tt is unsuit-
able for water based products
Pressure Process
1 Suitable for small to medium production
runs at moderate speed
2 Propellant losses are insignificant
3 Suitable for inflammable propellants
4 Filling IS completely anhydrous
5 No heat has to be removed initially and
less heat is therefore needed to bring the tem-
perature of the pack to 130* F
6 Suitable for water based products
Herzka, A , and Pickthall, I Pressurized Packaging (Aerosols) ed. 2 p 115 New York Acad Press
1961
In the pressure process, provision must
be made to evacuate or remove all of (he air
from the contamer, otherwise the air trapped
within the contamer will increase the final
pressure According to Dalton’s Law of
Partial Pressures, the total pressure, P will
be equal to the sum of the pressure due to air,
pi, and the vapor pressure of the propellant,
p2
P = Pl + P2
Smee the propellant is added prior to seal-
mg the valve m the cold process, the air is
expelled by the partial vaporization of the
propellant Both of these methods are used
satisfactorily m the laboratoiy and m produc-
tion for the fillmg of all types of aerosol
products The method of fillmg the com-
pressed gas products is similar to the pres-
sure process, and the gas is added through
the valve through use of a specially design^
nozzle and a reduemg gauge set to the de-
sired pressure as shown m Figure 105. For
dures mvolved m the large-scale production
of aerosol products bnefly, with special em-
phasis on medicmal and pharmaceutical
aerosols
The filling of aerosol products is accom-
plished through the use of specialized equip-
ment An aerosol filling plant combines the
standard manufactunng and fillmg equip-
ment found m most pharmaceutical plants
with the specialized equipment necessary to
pressurize aerosol products, and facihties de-
voted exclusively to the filling of all types of
aerosol products are available
A manufacturer who wishes to market an
aerosol product can do so m one of two ways
The entire operation may be set up and Uic
manufactunng and the packaging operations
done by the manufacturer concern itself On
the other hand, the services of a custom or
contract filler or loader may be secured and
the complete operation be performed by the
custom filler. If desired, the manufacturer
Fic 103 Addition of propellant by
pressure fdlmg process (Builders Sheet
Metal)
cussioD of the nature of the equipment is
bejond the scope of this chapter, however.
Figure 106 illustrates a semiautomatic aero*
sol filling line Phannaceulical and medicinal
aerosols can be produced on equipment of
either the rotary type (Fig 107) or the
straight line type (Fig 108) Pharmaceutical
and medicind aerosols arc generally filled
m a completely enclosed, air-coaditioncd
room kept under positive pressure Strict
quality control procedures should be adhered
to at lUl times
PHYSICOCHEMICAL PROPERTIES
OF PROPELLANTS
The propellant is one of the most important
components of the aerosol package It is said
Aerosolt
Fic 107 Rotary pressure filler (The KannJg Pak Corp )
to be the heart of the aerosol It provides the For purposes of this chapter the propellant
necessary force to C4pcJ the contents, it includes
causes the product to be dispensed as cither 1 Liquefied gases
a foam or a spray, depending on the formula' A Fluonnated hydrocarbons (halo*
tion * Also — with the exception of the com- carbons)
pressed gas propcifant — it serves as a solvent B Hydrocarbons
tor certain active ingredients 2 Compressed gases
According to the Chemical Specialties
Manufacturers Association, a propellant is Liquefied Gas Propellants
“A liquefied gas with a vapor pressure greater Fluonnated Hydrocarbons. The liquefied
than atmospheric pressure ( 14 7 psia) at a gases used as propellants arc essentially chio*
temperature of 105° F ” This indudcs sub- nnated fluonnated hydrocarbons of the
stances which m themselves cannot be used methane and the ethane senes and, more rc-
as propellants but which will give a sabsfac- cenUy, the butane senes These compounds
lory vapor pressure when they arc mixed havcbccauscdformanyycarsasrcfrigcranis
wiih a liquid of high vapor pressure This Their low boiling points and vapor pressures
dcriniiion is not all-incluswe, since it docs make them ideal for this putposc These
not cover the compressed gases Since the properties arc the basis for ihctr use as aero-
vapor pressure of some of the compressed sol propellants (impounds such os tnchloro-
gascs approaches 800 psig, for practical pur- raononuoromcthanc (Propellant 11), di-
poscs, they cannot be used as liquefied gases. chlofodiQuoromcihanc (Propellant 12) and
Fig lOS Straight line aerosol equipment (The KartridgPak Corp )
dichlorotctrafluoroetbane (Propellant 114)
are examples of some of the propellants
utilized in aerosol products Each propellant
has a constant vapor pressure at any given
temperature and by varying the propellant
vapor pressures from about 5 to 140 psig at
70® F can be obtained The wide range m
vapor pressure of these compounds their
relatively nontoxic property their nooin
(lammability and their noninitating char
actenstics make them safe and elective
propellants The U S Food and Drug Ad
ministration has already approved several
products containing propellants of these types
for spraymg into the mouth or the nose &ch
new product must be fully investigated be
fore It is gjien approval A relatively new
propellant known as octaQuorocyclobutane
IS reported to be nootoxic stable and suit
able for use m medicinal and food aerosols
and has been granted approval by the Food
and Drug Administration for use m whipped
creams and toppings
Nomenclature The fluormatcd hydro-
carbons (halocarbons) arc demed from
relatively simple chemical compounds
(methane ethane and butane) but it is
awkward to refer to substituted compounds
by their complete chemical names — for ex-
ample dichlorodihuoromethane dichloro
tetrafluoroethane etc For this reason the
refrigeration mdustry has adopted a number
mg system which is used to designate the
various fluorinaied hydrocarbon propellant
compounds *
1 All propellants are designated by three
digits
2 The first digit on the nght is the number
of Quorme atoms m the compound
3 The second digit from the nght is one
more than the number of hydrogen atoms m
the <x>mpound
4 The third digit from the right is one
less than the numter of carbon atoms in the
compound When this digit is zero it is
omitted from the number Therefore two
digit numbers indicate methane dcnvativcs
5 The number of chlorine atoms in the
compound is found by subtracting the sum
of the fluorine and the hydrogen atoms from
the total number of atoms which can be
added to the carbon cham
6 In the case of isomers each has the
some number and the most symmetric one
IS indicated by the number alone As the
isomers become more and more asymmetne,
the letter a b ceic follows the number
7 Where the compound is ^dic, a C is
260 Aerosol*
Fic 109 Range of vapor pressure* obtainable with various mixtures of propellants at
70* F
used before the number The following is an
example of the use of this system
PROPELLANT 12 — ^This contoins two
fluorine atoms (last digit) and no hydrogen
atoms (second digit from right is one more
than number of hydrogen atoms) Since it is
a tHO>digit number (zero is understood be*
fore the first digit), this compound is a
methane dcnvativc Since four atoms con be
attached to this carbon and only tss-o fluorine
atoms arc present, there must be two
chlorine atoms Therefore, the compound is
dichlorodifluoromcthanc
a
F— i:— F
i.
Table 38 indicates the relationship between
the chemical name and the number of some
of the commonly used propeUants In the
following discussion these compounds will
be referred to as Propellant 1 1, Propellant 12
etc. In the UnneJ States these compounds
arc available under the following trade names.
Frton — Freon Products Division, E I
du Pont de Nemours and Company
Cenetron — General Chemical Division,
Allied Chemical Coip
isotron — Industrial Chemicals Division,
PennsaJt Chemical Corp
Ucon — Union Carbide Chemicals Com-
pany, Union Carbide Corp
Physical Properties of Propellants
Several of the more unportant physical prop-
erties of the fluormated hydrocarbons arc
in Table 39
Vapor Pressure The fluormated hydro-
Table 38 Numerical Designation of Fluorinated Hydrocarbons
CiicMiCAL Name
Chemical
Formula
Numerical
Designation
Tnchloromonofluoromcthane
ca,F
11
Dichlorodifluoromcthanc
CQjF,
12
Monochlorodifluoromclhanc
CHOP,
22
Dichlorodifluorocthane
CCIFXaFj
114
osy Dichlorodifluorocthane
Ca-FCFj
]I4a
Monochlorodiiluoroc thane
CHjCaFs
142b
Difluoroclfaone
CHjCHF,
J52a
Octofluorocyclobuiane
CF.CF-CFjCFa
C-318
Table 39 Physical Properties of Fluorinated Hydrocarbons
(volume per cent m
Qir) noninflam noninflam nonmflam 5 1 17 1 9 0 14 8 noninflam
Toxicuy (U L, rating
system) 5A 6 6 5A 5At 6t
• psig 4-14 7 = psia t Probable t Preliminary Value
262 Aerosols
Fio 110 Vapor pressure vs tcmpcralurc (E 1 duPont dc Nemours and Co , Inc )
carbons arc gases at room temperature but
their vapor pressure is low enough so that
the;/ may b« hs^vst&eii casvly Vapor prcsssitt;
IS defined as the pressure exerted by a gas
or a vapor when it is in contact with the
liquid or llic solid phase of the same ma-
tcnal * This is constant for any given ma-
terial at a given temperature The lluonnatcd
hydrocarbons arc unique in that they exhibit
a range of vapor pressures when blended
Figure 109 shows the extent of vapor pres-
sures obtainable with the various available
fluonnated hydrocarbons
As the temperature of the fluonnated hy-
drocarbons IS increased, die vapor pressure
will increase, since a greater number of
molecules will exist m the vapor state at
elevated temperatures as compared with
lower temperatures Since an cquilibnum
txvsts bc\wetn number ol
changing from the vapor state to the liquid
slate and from the liquid state to the vapor
stale, a temperature is soon attained where
the propellant can exist only in the gaseous
state This IS known as the critical tempera-
ture However, aerosols of the liquefied gas
type depend on the condmon that the vapor
phase in equilibrium with its liquid state
For practical purposes, the vapor pressure
considerations very seldom exceed tempera-
tures of 130® F Figure 110 shows the effect
of temperature on the vapor pressures of a
number of different propellant compounds,
and Figure 1 1 1 shows this same rclaponship
physicochemical Properties of Propellants 263
Fig 111 Pressure temperature relationship of Freon 12/11 solutions (E I duPont de
Nemours and Co . loc )
with commonly used propellant blends The sure is equal to the sum of the mole fractions
Lilect of varymg the amount of each com- of each component present, multipLed by the
pooent of the propellant at vanous tempera- vapor pressure of the pure compound at the
lures IS shown m IHgure 1 12 desired temperature Expressed mathemat-
Whtlc the vapor pressure of the propellants ically
remains constant at any given temperature,
the vapor pressure can & “custom made” = N^Pao
by blendmg vanous propellants having dif- + na
ferent vapor pressures This has been shown
graphically m Figures 111 and 112, how- where
ever it IS possible to calculate this reJa- ^ Component A
Uonship Roault s Law states that the vapor _ >apor pressure of pure Componeni A
pressure of a soluuon is dependent on the _ number of moles of Component A
vapor pressure of the mdividual compo- On = number of moles of Component B
nents For ideal solutions, the vapor pres- N, =; mole fraction of Component A.
Fia 112 Vapor pressure — compos j oa of Ocnciron 12/J 14 macs (Allied Chem cal Corp
Ocncral Chemical Division)
The total vapor pressure of the system is
then obtauicd by
V P = p, + Pb
This )s best shown by referring to the follow
lOg example
Calculate the vapor pressure at 70* F of
a solution consisting of 60 per cent by weight
of Propellant 1 14 and 40 per cent by weight
ofPro^Uant 12
To calculate the moles of each substance
present
moles - - 60
“ “mW 1709
£=03511 moles Propellant 114
Similarly
40
• = 0 3309 moles Propellant 12
Total number of moles
0 3511 + 0 3309 = 0 6820 moles of
Propellant 114/12
Fia 113 Density of aerosol propellants (Allied Chemical Corp General Chenucal Div )
Mole fraction of Propellant 1 14
Moles of PropeUant 114 0 3511 ^
Total Moles 0 6S20
Mole fraction of Propellant 12
Moles of Propellant 12 03309
£ = = 0 481
Total Moles 0 6820
Partial pressure of Propellant 1 14
Mole fraction X V P = 0 5149 X 27 6
= 14 21 psia Propellant 1 14
Partial pressure of Propellant 12
Mole fracuon x V P = 0 4851 X 84^
= 41 18 psia Propellant 12
Total pressure of system
14 21 + 41 18 = 55J9 psia (absolute)
To obtain gauge pressure
55 39 — 14 7 = 40 69 psig (gauge)
The results of these calculations generally
differ slightly from the experimental results
since It IS assumed that the solutions are
ideal in behavior As the second component
becomes smaller and smaller the behavior
approaches ideal conditions
In any given senes of fluonnated b)dro
carbons as the number of fluorme atoms m
crease the boiling point will decrease and
the vapor pressure will increase This can
be seen from Table 39
Density These matenals vary m density
from 0 911 to 1 513 Gm /ml Generally, the
density of the compound mcreases as the
number of Quonne atoms mcrease This holds
true for any gnen senes of compounds In
266 Aerosols
Fio 114 Density of propellant 12/11 solutions (Chemica] Corp General Chemical Div )
many instances the amount of propellant to
be used 10 a given formulation is expressed
m terms of weight Howcicr it is somelrmes
more comement to measure these quantities
on the basis of volume, and the density would
be used to calculate the volume from the
weight Figure 113 shows the densities of the
various aerosol propellants at diflerent tern
peraturcs The densities of the vanous blends
of Propellant 12 and Propellant 11 are
given m Figure 114
For the most port the hquid density i5 un
portont In the case of liquefied gases, the
density of the propellant in the vapor state
IS equally important Depending on the size
of the contamcr the w-cight of the propellant
m the vapor state becomes significant Figure
1 15 shows the vapor densities of Propellants
Hand 12
Heat of Vaponjiiion When an aerosol
product IS dispensed from a container, the
volume of the head space increases, causmg
a temporary drop m pressure Immediately,
some of the molecules in the hquid state
change to the vapor state to restore the
ongmal pressure In so domg heat changes
take place If the discharge is rapid, then
this heat change is noticeable m that the
temperature of the package is lowered. The
heat of vaporization for Propellant 11 and
Propellant 12 is shown m Figure 116 In
the cold filling process a knowledge of the
heat changes mvolvcd are important so that
proper equipment may be utilized
Solubility Characteristics The fluonnated
hydrocarbons arc relatively nonpolar organic
liquids and arc good solvents for materials of
similar types They arc not miscible with
the highly polar compounds such as water
The fluorocarbons have solvent qualities
simibr to those of the chlonnated solvents
such as carbon icirachlondc However, there
Physicochemical Properties of Propellants 267
Fio 116 Saturated liquid and vapor heat content. (Z^/r) Propellant 1 ! (Right) Propellant
12 (AlLcd Chemical COrp Geoer^ Chemical Oiv )
268 Aetosols
Table 40 Stabilizisg Effect of
FLLOKINE ATOMS
COMrOUND
Formula
Carbos-Oilo-
FIVE Bond
Distance (A)
Methylene ch!o-
ndc
cH cr.
I 77
Carbon tcira
chloride
CCI4
176
Propellant 22
CHCIF3
1 73
Propellant 1 2
CCUFj
1 70
IS enough difference so that direct compan-
son IS not too helpful The solvent power of
the duoruiatcd hydrocarbons ranges from
poor for the highly fluorioatcd compounds
such as Propellants 12 and 114 to fairly
good for those contammg less fluorine — such
as Propellant 11 Fluonnatcd compounds
than the other compounds and, therefore,
cannot be used for aqueous preparations
CCIjF + H 3 O HCl + CHasF
Table 41 contains selected mformatioo as
(o the hydrolysis of some of the commonly
used propellants From this table it can
seen that, in regard to hydrolysis, Propellant
11 IS the least stable, and, uhilc Propellants
12 and 114 ore stable, the completely fluo>
nnated Propellant C-318 has about 1/20
the hydrolysis rate ol Propellant 12 The
hydrolysis rate is increased in the presence
of alkaline maienals and, therefore, is a
function of the hydroxyl ion concentration
An increase in temperature will also increase
the rate of hydrolysU
Another reaction uhich has been the cause
of corrosion in metal contamers is the rc>
action of Propellant 1 1 with ethyl alcohol
CCIjP + CjH.OH f CH 3 CHO + HO + CHCIjF
acetaldehyde
CHjCHO + ZCjH.OH » CH,CH(OC,Hs), + HjO
acetal
CjHjOH + Ha CsHjCl + HjO
comaiomg other halogens axe usually better
solvents than the completely fluonnatcd com-
pounds Generally, compounds with a low
molecular weight arc more soluble m the
fluonnatcd hydrocarbons than Uiose with
high molecular weight
CiiEMiCAi Properties The fluonnatcd
hydrocarbons are noted for their chemical
mcrincss They arc, for the most part, non-
rcactivc The general reaction w-hich may
take place invoHcs the carbon (o-lialogcn
bond Ithos been established that the fluorine
Imkcd with a carbon atom mcrcascs the
stability of the other halogens attached to the
same carbon atom This nuy be demon-
suated by measuring bond distances Gen-
erally, the shorter the bond distance, the
greater the energy required to rupture the
bond Table 40 gives some of the carbon-
to-chJormc bond distances
The reaction becomes important m the
presence of water, for hydrolysis wiU take
place, resulting m the formation of acids
which arc corrosive to the metal contamcr
and the metallic parts of the valve Propel-
lant 11 shows a greater rate of hydrolysis
It has been estimated that this reaction takes
place to the extent of about 7 per cent The
acculdchydc and acetal are corrosive in
action Sanders'*" has noted that this is a
typical free radical reaction and requires the
presence of a catalyst It was concluded that
this reaction could be prevented by the addi-
tion of a suitable stabilizer This led to the
formulation of a * stabilized ’ Propellant 1 1 S
which IS Propellant 1 1 with the addition of
3 stabilizer such os nitromcthane This is
sulflcicnt to prevent the reaction
Propellants 11, 12 and 114 arc commonly
used in all aerosol formulations They arc
suitable for use in pbannaccutical and me-
dicinal aerosols os well Propellant 11 has
a greater solvent range than the others, how-
ever, hydrolysis m aqueous media limits its
use Propellant 12 is used to a great extent
for mcdicmal acrosob, since the desired par-
ticle size is produced when used with a
specially designed applicator
Recent investigations by Tinncy and
Sciarra'" have shown that Propellants 142b
and lS2a arc suitable for use in medicmal
aerosols Propellant I42b and Propellant
Physicochemical Properties of Propellants 269
Fio 117 Propellant vapor extinguishing a flame (E. J duPont dc Nemours and Co Inc)
I52a have been found to be good solvents
foe some of the commooly used medicinal
agents such as ephcdrine, atropme and
tnpclcnnamme These propellants arc less
prone to hydrolysis than Propellant 1 1 and
cause less imtalion While Propellant 152a
tends to be slightly more inflammable than
some of the other propellants, the quantity
of propellant used m medicinal aerosols is
extremely small so that inflammability is not
considered to be a problem
Another propellant showing promise of
use for medicinal and pharmaceutical
aerosols IS Propellant C 318 Thiscompound
has been developed for use m food aerosols
but may be applicable to medicinal uses It
IS free from hydrolysis and has an extremely
low toxJCJiy
An additional feature of the fluormated
hydrocarbons is their nonmflammabihty In
fact, they have been used as fire extinguishers
The vapors are heavier than air and will form
Table 4 1 Rate of Hydrolysis of Several Compounds
(Grams of Propellant Hydrolyzed/Liler of Water/Vear)
One Atmosphere Pressure — 86* F
1 Per Cent
Compound
Water Alone
Water + Steel
Water + Copper
Sod Cars
Propellant 1 1
<0 005
19 0
0 IS
012
Propellant 12
<0 005
08
0 005
004
Propellant 21
<0 01
52
0 38
330
PropcUaot 114
<0 005
I 4
0005
0 01
Propellant 22
<001
014
0 02
220
Note The rate of Propellant C-31S was found to be 22 mg.Mitcr of 10 ptf ceal Sodium
Hydroxide so|uijoa/}ear
270 Aerosols
Tadle 42 PifYsiCAL Properties of Compressed Gas Propellants
Propellant
Carbon
Dioxide
Nitrous
Oxide
Nitrogen
AIR
Chemical formula
COj
N.O
N,
Na + O,
Molecular w eight
44
44
28
29
Boiling point *F
-109*
-127
-320
—
Vapor pressure, psia,
70* F
852
735
492t
Solubility in water, t
77* F.
07
05
0 014
0017
Limit of inflammabiliiy
nonflam
nonllam
nonflam
nonflam
Toxicity, UL. rating
system
5
6
6
Density (gas) Gm /ml
U3
1 53
0 96699
—
* Sublimes
t At Cntical Point (-233* F )
t Volume of gas si atmospheric pressure soluble in one solume of water
a blanket around the flame uith the exclusion
of oxygen This unique property is shovm in
Figure 117
Hydrocarbon Propellants. The hydrocar*
bons (butane propane and isobutane) base
not been utilized to date for pharmaceuucal
and medicinal aerosols While their low order
toxicity makes them suitable for use, their
odor, taste and high degree of inflammability
discourage their use for (his purpose How*
e>cr, mixtures of hydrocarbons and fluor*
mated hydrocarbons have been investigated
and found to be less inflammable than the
pure hydrocarbon ^
Compressed Gas Propellants
Of the nonhqucfied compressed gas pro-
pellants, nitrogen has found the greatest use
its insolubility and inertness ha>c made it the
propellant of choice uhen dispensuig certain
pharmaceutical products m their onginal
form such as vitamins, ointments and creams
It IS possible that the future development of
suitable actuators and baffles may allow the
use of nitrogen and other compressed gases
as propellants for medicinal aerosols Since
the size of the particles must be well below
10 microns for inhalation therapy, an elHacnt
baffle IS necessary Present-day technology in
this area precludes the use of the compressed
gases for this purpose
Other compressed gases finding use for
pharmaceutical preparations arc nitmus
oxide and carbon dioxide These are known
os soluble compressed gases and are used for
a vanety of purposes Being soluble in the
product eoncentratc, they cause the product
to expand when emitted from the container
If the product is emitted through a foam type
valve, a foam is produced A fine mist can be
obtamed through utilization of a mechanical
break up actuator and a nonfoaming product
concentrate The type of formulation will
determine the dispensing charactensucs of
the product Formerly, a compressed gas pro-
peUant was used to push the material through
the valve and dispense it in its original form
Nitrogen was used for this purpose Recently,
It was found that by usmg a soluble com-
pressed gas and a spray nozzle, the product
could also be dispersed as a wet spray
The pressure developed by a compressed
gas IS dependent largely on the temperature
and the amount of gas present The ideal gas
fonnula may be used to express the rclaiton*
ship
PV = nRT
where P = pressure m aUnosphcrcs, V =
volume in Iiien, n = moles of gas (Gm /
hf W ), R =: universal gas constant
(008205 liter aimosphcrcs/dcgrce/molc)
and T= absolute temperature (®C -4*273)
This can be used to caioilate pressure
Physicochemical Properties of Propellants 271
Table 43 Underwriters’ Laboratories
Classification of Toxicity
Classification
Definition
1
0 5 to 1 vol % , senous injury
in 5 mmutes
2
0 5 to 1 vol %, senous injury
m 30 minutes
3
2 to 2 5 vol % , senous injury
m 1 hour
4
2 to 2 5 vol %, senous injiuy
ui2houK
4-5
Less toxic than 4 but more toxic
than 5
5a
Much less toxic than 4 but
more toxic than 6
5b
Data indicate cla&smg as 5a or 6
6
20 vol % , no mjury lo 2 hours
From Reed, F T Toxicity of propellxnts,
Amencaa Perfumer 7S 42, 1960
changes taking place as a compressed gas
aerosol is dispensed ^Vbereas a liquefied
gas aerosol maintains a constant pressure
throughout the life of the product, a com
pressed gas aerosol will show a drop m pres*
sure For example, 6 Buidouaces of a tooth
paste concentrate are placed m an 8-fluid-
ounce contamer and pressurized ^vlth nitro-
gen to 90 psta, when 2 fluidounces of product
have been dispensed, the pressure falls to
approximately 45 psia (Boyle’s Law) If the
product contained a soluble compressed gas.
the pressure change would not be as great.
Some physical constants for the commonly
used compressed gases are shown m Table
42
Nitrogen is chemically mert and has been
used for many years to prevent the oxidation
of pharmaceuticals This property adds to its
effectiveness as an aerosol propellant Nitro-
gen IS generally prepared by liquefaction of
air followed by separation of the rutrogen
from the oxygen and the other components
of air
It IS used mainly for those aerosol products
mtended for dispensmg as a solid stream m
ihcir ongmal forms As such, it is useful for
many semisoUd prcpacatioru and viscous
liquids
Nitrous oxide is stable m the presence of
most oxidizing agents It is gencr^y used m
combmation with carbon dioxide as a pro-
pellant for whipped cream and loppings A
Table 44 Toxicity Rating of Several
Commonly Used Substances
CoMPoinvD
V L
Classification
Maximum
Allowable
Concentration
SO 2
1
10 ppm
NHj
2
1 00 ppm
ca*
3
25 ppm
CH 3 O
4
lOO ppm
From Reed F T Amencaa Perfumer 75 42
I960
recently introduced aerosol utilized this com-
bination as the propellant for a chocolate-
flavored syrup Its latest use is m the formu-
lation of a velennaiy product for mastitis,
to dispense the product as a foam.
Carbon dioxide is considered to be a
stable and relatively mert gas However, it is
soluble in water to w'hich it imparts an acid
pH
In many food products such as fruit-
flavored syrups the acid pH is desired, since
It imparts a tart taste to the product In addi
uon to Its use as a food propellant, carbon
dioxide has been used to formulate the de-
icer type aerosol sprays
Toxicity of Propellants
The Underwriters’ Laboratories have m-
vestigated the toxicity of several of the fluo-
nnated hydrocarbons and reported their find-
ings for groups The Laboratories system of
classificauon is given m Table 43 Table 44
gives the classifications for some commonly
used chemicals, and Table 45 presents the
results of the Underwriters’ Laboratories
studies ^ Propellants 12, 1 14 and I52a have
been placed in Group 6 and are rated as less
toxic than carbon dioxide Considering that
air IS a member of Group 6, it is apparent
that materials classified m Group 6 may be
used safely as propellants
However, a danger to the manufacturer of
the propellants and to the aerosol loader
would exist should these materials displace
the oxygen m the air Smee the propeUants
will not support life, precautions must be
taken to ensure an adequate air supply
Smcc many of these products are used
topically, skm sensitization to the commonly
used propellant compounds should be con-
272
Aerosols
Table 45 Classification of
Propellant Compounds
Propellant
U L. Classi
FICATION
Max. Allowable
Concentration
11
5a
I OOOpptn
12
6
I 000 ppm
21
5
1 000 ppm
22
Sa
1 000 ppm
114
6
1 000 ppm
142b
Sa
—
I52a
6
—
C 318
6
I 000 ppm
CO,
Sa
5 000 ppm
N 0
—
—
N,
6
—
Air
6
—
Propane
5b
I 000 ppm
n Qulane
5b
1 000 ppm
i Butane
5b
1 000 ppm
Adapted from Reed F T Americaa Perfumer
75 42. 1960
stdercd Very liiilc data are available on these
compounds as to skin scosiuzatjon However,
to date, very few, if any, cases of skin sensi-
tization have been reported In rabbit-e)e
tests which were conducted. Propellants II,
12 and 114 caused no reaction While the
concentration of propellant used m each test
was low, lack of toxicity was indicated for
this group of compounds
TTic liquefied gas propellants arc refriger-
ants and may cause frost bite if they are
sprayed on a skin area for a prolonged period
of time This is unlikely to occur, since the
initial chilling effect would serve as a warn
ing Very litUe is known as to the quantita
live temperature changes taking place on the
skin when an aerosol product is sprayed
over an affected area Studies by Dunne“ led
to the following conclusions *
* Dunne T F Deiermioauoa of pou ble chill
ing effects of propellants Aerosol Age 4 36 1959
Fia 118 Three piece im-coated cootamers (Continental Can Co )
Aerosol Valves
273
Fig 119 Two piece drawn containers
(Spra tamer)
1 The chilling effect of a s)Stem ts generally
less than that of the pure propellant However
at propellant concentrations of 70 per cent and
above the chill ng effect may be greater than
that of the pure propellant
2 The chilling effect increases as propellant
concentration increases
3 The chilling effects of propellant solvent
systems for a given solvent are in the same
relative order as the pure propellants
AEROSOL CONTAINERS
The containers used for pharmaceutical
and medicmal aerosols arc similar to the
usual type of aerosol containers Aerosol or
pressure contamers generally fall into one
of the following categories
1 Metal
A Tin plated steel
a Side seam (three piece)
b Two piece or drawn
B Aluminum
a Two-piece
b Extruded
C Stainless steel
2 Glass
A Uncoated glass
B Plastic-coatcd glass
3 Synthetic resins and plastics
All of the materials listed above have been
used in the construction of aerosol containers
Pharmaceutical and medicmal aerosols are
packaged m many of these containers
Figures 118 to 123 illustrate several of these
containers
AEROSOL VALVES
During the development of the aerosol m
dustry many new and challengmg problems
Fic 120 IVo-picce alummum aerosol
container (Continental Can Co )
274 Aerosols
Fio 121 Stainless steel containers for
medicinal aerosols
were encountered As the various aerosol
products were developed the shortcomings of
the technology m various areas became ap>
parent Howeser, once a problem presented
Itself, ways and means to overcome the dilTi-
cultics were immediately investigated The
development of vanous t)pcs of propellant
eompounds and the technology involved in
the development of the various aerosol con
tamers have been discussed m the preceding
sections The development of the aerosol
valve was not dilTcrcat Here, too, many
problems were apparent smcc the valve roust
perform various functions ’
1 The valve must be capable of reieasrog
the product promptly and of stopping the
(low quickly
2 ft must be capable of dispensing the
product in the desued physical form, whether
or not this requires a change m the onginal
form. For example, insecticides arc dispensed
as fine spra)s or mists, shaving creams as
foams, and tooth pastes m their ongmal form
While the nature of the formulation and the
type of propellant used have an influence on
the dispensing charactcrutics, it is the valve
which ultimately determines the form of the
dispensed product
3 Certam applications require that the
flow of product M accurately controlled—
that IS, only a given amount of product must
be dispensed This is especially needed for
mcdicmal aerosols and several pharma*
ceutical aerosols
Vanous aerosol valves have been dc-
V eloped and include the following
I Non metered valves
A Liquefied gas
a Spray
b Foam
B Compressed gas
a. Spray
b Foam
c Solid stream
2 Metered valves
A Liquefied gas
a Spray
b Foam
B Compressed gas
a Spray
b Foam
c Solid stream
hfost of the valves listed above arc avail-
able for use on both metal and glass con-
tainers A few can be used only on metal
coDiauicrs, due, mainly, to certain restne-
tions placed on the size of the valve proper
Spray Valves. Most spray valves arc com-
posed of certam basic parts, consisting essen-
tially of an orifice which opens into a cham-
ber There are generally two or three of these
onfices and chambers m each valve The dis-
ch:ugc rate of the product is controlled, for
the most part, by the size of the smallest in-
ternal onfice while the dimensions of the ex-
ternal onfice generally determines or influ-
ences the degree of atomization As the liquid
passes from one onfice to another, it expands,
causing a drop m pressure which results m a
partial vaporization of the liquid. This process
1 $ repeated at the other onfices, the vaporiza-
tion of propellant becoming more violent at
each orifice and resulting m a complete
atomization of the product at the final orifice
This spray type vajve will dispense the con-
tents of the contamcr continuously as long
as the valve is left m the open position
In addition to the onfices, the valve is
made up of an actuator button, a valve core,
a natural or synthetic rubber gasket seal, a
valve cup, a stainless steel or nylon spring,
and a dip tube Figure 124 shows such com-
ponents and their relation to each other The
gasket prevents the liquid phase of the
product Jrom flowing through the valve stem
by scaluig it when the valve is m the closed
position Tension on the valve stem is main-
tained by the sprmg. When finger pressure is
applied at any point on the side of the
actuator, the valve core is deflected from the
scat This exposes the onfice to the product
concentrate, thus allowmg access to the ex-
Fig 122 Class aerosol contaioen (Foster Forbes Glass Co )
276 Acrotols
paosion chambers \vithia the valve core
Other valves operate by depressing the actu-
ator rather than by a tilting action.
The product and the propellant come into
intimate contact with most parts of the valve
and steps must be taken either to choose ma-
terials that are not alTccted by the propellant
or the product concentrate or to protect those
components which will be affected with suit-
able coatings Throu^ use of an appropnatc
actuator the product can be dispensed in a
vanety of ways using this t}pe of valve
Foam Valves. The valve described m the
precedmg paragraphs can also be used for
foam products However, a simpler t)pc is
useful and allows for a greater flow rate
These valves generally consist of a valve
stem inserted through a rubber or rubbcrlike
gasket When the valve stem is tilted or de-
pressed, the valve scat is no longer in con-
tact with the rubber gasket and the product
IS allowed to flow through the openings
Metered Valves. A valve that dispenses a
predetenmned quantity is highly desirable
for medicinal aerosols the dosage of which
must be controlled withm narrow limits
These valves may be designed m one of the
follow mg wa)s
1 Double chamber system
2 Stainless steel ball check
3 Flexible chamber type
4 Rigid chamber type*-
The valves ore capable of accurately dis-
pensing from 50 to 150 mg of propellant
with active ingredients Tlus amount will vary
somewhat, depending on the density of the
concentrate These valves can be used only
with liquefied gas propellants They have
been used successfully for perfumes, colognes
(I) Dual Onficc. (k) Groove (Rxsdoa Manufacturing Co )
Pharmaceutical Aerosols 277
and medicinal aerosols In addibon, they are portance when the omtment is to be applied
useftil for both spray and foam products, to irntated, or diseased skm or denuded
dependmg on the formulation and the actu- areas The smaller the particle size of the
ator Other types of metered valves can be medicament, the less is the preparation likely
used for both liquefied and compressed gas to cause further imtation Such a reduction
aerosols m particle size can be accomplished by a
liquefied gas aerosol formulation m which
PHARMACEUTICAL AEROSOLS dispersion of particles from the actuator
is withm the range of 30 to 50 imcrons or
These products have been developed as less With the reduction both m particle size
fine sprays, foams, powders and semisohd and m thickness of the matenal to be apphed
preparations Smce they are used topically, to a given area, penetration of medication
local irritation is an important consideration mto the ducts of the skm can be accomplished
Other considerations, as outlmed by Porush’* without vigorous rubbmg
are as follows Ethyl alcohol is a good cosolvcnt and is
1 Compatibility of component mgredients useful m many types of pharmaceutical aero-
2 Wetness or spray chaiactenstics, m- sols It is miscible with the usual propellants
cludmg rate of propellant and cosolvent and is relatively free of dermal toxicity How-
evaporaiion ever, alcohol is not suitable for application
3 Stability of the drug m contact with the to large areas of broken, abraded skm or
contamer and valve parts burned areas, smce it causes a stmgmg sensa-
4 Effect of the aerosol solution and drug tion Other cosolvents such as propylene gly>
on the contamer and the valve (mcluding col,polypropylenegl)col,isopTop)lmynstate,
corrosion of metals and detenoration of polyethylene glycols, some fixed oils, glyc-
gaskets) erm, hquid petrolatum, hexylene glycol and
5 Appraisal of dermal toxicity several of the diethylene glycol monoall^l
6 Clmical evaluation of the drug ethers may be used General formulas which
The classification of vanous omtment bases van be used as a startmg point for the formu-
and the absorption of medicmals from these lation of two phase pharmaceutical aerosols
bases has been discussed elsewhere How- follow
1 AcUve iDgredicDls 10% by weight
PropeUants 12/11 (50 50) 90%
ever, m regard to the use of pharmaceutical This can be used to formulate medications
aerosols, it is of mterest that, accordmg to for athlete’s foot, bum remedies, wound
Fuller, Hawkins and Partridge,®' the funda medication etc The amount of active m-
mental consideration m the absorption of gredients may be vaned to suit mdividual
substances from omtments is the ratio of needs
2 Active ingredients 1 5% by weight
Solvents 10%
Propellants 12/11 (50 50) 85 89%
the surface of the preparaUon to its volume ” This can be used for the products listed under
If the surface is relaUvely large — as m a thm Formula 1 The solvents tend to decrease the
film lajer the delay from oil preparations chilhng effect as well as to leave behmd a
IS small, this is found when omtments arc thm film or residue, depending on the nature
smeared over a large surface In this connec- of the solvent
Uon it seems that an aerosol omtment ptep- An emulsified or foam system has been
arauon is advantageous, smce it will coat a used to great advantage for the dispensmg
large area of the body with a veiy thm film of therapeutically active mgredients which
of medication irritatmg or otherwise hannful if m-
Particle size is always important m omt- haled It is also useful for those applicauons
ment preparauons It is of even greater im- m which the chilling caused by the rapid
[ 278 1
Variation of propcUaot conceniraiion may yield pro[>er spray
rromSciarra J J r/al Drug Standards 75 20 1960
280 Aerotolt
cvaponiUOD of the propellants presents a
problem For the most part, foam aerosols
contain a considerably smaller quantity of
propellant Depending on the t}*pe of for>
mulatjon, the foam may be q^uick breaking
or stabilized. The quick-brcakiog foam for>
mulatioQ IS useful uben products arc used to
cover a large area or when rubbmg is not
desirable — as m treatment of extensive areas
that have been burned or denuded The me*
chaoical application of medication together
with the abrasion caused by spreadmg the
product over the aiTcctcd area may cause
further damage The stabilized foam prepara-
tion IS useful for many topical preparations
when penetration of the acuve mgredieots
IS enhanced by rubbmg Many sterol and
steroid preparations are dispensed m this
manner
In on attempt to determine some of the
principles involved m the formulation of
emulsion tv pc topical preparations, Sciarra,
Tinncy and Fccly"‘ investigated several typi-
cal ointment bases m combination with sur-
factants One senes consisted of an ointment
base and a propellant while the other senes
consisted of an omtnicnt base, a propellant
and a surface active agent The dispcnsmg
characteristics arc shown m Tables 46 and
47
The addition of a surfacc-acUvc agent to
the propcllant/oinuncnt base mixture m-
creased the stability of most of the products
insofar as separation of ingredients is con-
cerned In those cases where a foam type
spray was produced, tlic foam quickly col-
lapsed, releasing llic base m its original fonn
This IS believed to be an ideal method for
the administration of raediciaol ingredients
over a large area, since no spreading or rub-
bing IS required m order to bnng the base
and the medicinal agents in contact with the
alTccted areas of skin No attempt was made
durmg this study to alter the propellant con-
centration in order to produce diflcrcnt types
of spray s and foams
Further investigations were earned out m
the laboratories of Allied Chemical Corpora-
tion, General Chemical Division, as to the
formulation of quick-breaking foams •• A
basic formulation for a quick brcakmg foam
IS as follows
Ethanol 46 0-66 0%
Surfactant 05- 5 O'e
Water 28 0-42 0%
Propellant 3 0-15 0%
The proportion of surfactant m a quick-
breabng foam is between one half and one
twentieth of that employed in formulations
for the stabilized foam products
According to investigations earned out m
the labointones of the E I du Pont de
Kemours and Company, nonaqueous aerosol
foams may also be formulated.^® Glycols and
glycol dcnvaiivcs have been substituted for
water in conventional formulations By
proper selection of the glycol, the surfactant
and the propellant, foam stability may be
vaned to obtain very stable foams or quick-
breaking foams The use of aerosol foams
has been suggested for vaginal foams, oint-
ment bases, bum preparations and other
topical aerosols
A suggested starting formulation for non-
aqueous foams IS as follows
Glycol 86%
Emulsifying agent 4%
Propellant 12/114 (40 60) 10%
An ointment base formulation may co:
sist of
PoIycihyJcne glycol 400 86%
Propylene glycol monoslearate S E 4%
Propellant 12/114 (40 60) 10%
Antibiotic preparations have been fotmu-
laxd using a foam type aerosol The follow-
uig IS a general formula which may be used
for this purpose
Foam base 90%
Active ingredients 2%
Propellant 12/114 (40 60) 8%
A typical stabilized foam base is composi
of the following **
Part A Mynstic acid 133%
Slcanc acid 5 33%
(triple pressed)
Cetyl alcohol 0.50%
Lanolin 0 20%
Isopropyl my ristale 133%
PoftS Tncibanolamine 3 34%
Glycerin 470%
PVP 034%
Water, puniled 82.93%
Pharmaceuticol Aerosols 281
It IS prepared according to standard phar
maceuticd technics and pressurized using the
pressure method
The suspension or the dispersion system
has been used to great advantage m the dis-
pensmg of powders, mcludmg antibiotics and
steroids The propellant quickly evaporates
and leaves behmd the finely dispersed pow-
der Major difficulties whidi accompany the
formulation of this type of aerosol product
are valve clogging brought about by an ag-
glomeration of ffie msoluble particles and
the setthng out of the therapeutically active
ingredients These problems have been over-
come through the use of specially designed
aerosol valves together wiffi suitable lubri-
cants and dispersing agents In regard to the
latter, isopropyl mynstate has been used to
the greatest extent m preventing the agglom-
eration of the msoluble particles Other sub-
stances which have been used successfully or
axe currently under mvestigation are liquid
petrolatum, propylene glycol, lanolm and its
denvauves, steanc and mynstic acids and
steanc and mynstic alcohols Most of the
usual pharmaceutical suspendmg and dis-
persing agents, such as acacia, tragacanth,
methylcellulose etc , cannot be used, since
they are incompatible with the propeUants
An example of this type of system is as
follo\^s
AcUve ingiedients (insoluble) 0 S%
Suspending and dispensing agents 0 5%
Inert powder such os Talc (3S0
mesh) 100%
PropeUant 12/11 (50 50) 890%
This can be used for dispensing a vanety of
topical preparauons mcludmg medications
for athlete’s foot, first aid preparations and
antibiotics
Several vitamin preparations have been
formulated as compressed gas areosols Pom-
erantz suggests the following
per 06 ml
Thiamine hydrochlonde
RiboQavux (phosphate sodium
1 Omg
salt)
I Omg
Niacinamide
50 Omg
Panlhenol
1 Omg
Pyndoxide by drochlonde
2.5 mg
Ascorbic acid
40 Omg
Vitamin A
5,000 1 U
VitammD 1,000 1 U
Vitamm Bja 1 0 meg
This IS dispersed m a base of
Tween 80 10 0%
Sodium benzoate 0 2%
Water qs 100 0%
After packagmg m a glass contamer, it is
pressurized with mtrogen to 90 psig
Classificatios of Aerosol Pharma-
ceutical Preparatiovs
A recent survey of aerosol pharmaceutical
products found that aerosol pharmaceuticals
were available for many different uses
A listmg of pharmaceutical aerosols which
supplies the name of the manufacturer, as
well as type of aerosol, composition and use,
IS also go en “
Local Anesthetics. A variety of chemical
compounds bavmg local anesthetic proper-
ties have been utilized as the active mgredi-
ents for this type of aerosol Benzocame,
ethyl chloride, tetracame, naepame, ^clo-
methylcame and pramoxine hydrochloride
are only a few of the local anesthetic agents
which have been used In addition, Propel-
lant 1 14 alone, ethyl chlonde and Propellant
114 and Propellants 12/11 have been used
for their local anesthetic properties
Anliscptics, Germicides, Dismfectants and
First Aid Preparations. The nature of the
active mgredieuts used m aerosol prepara-
tions of this type vanes from the simplest of
antiseptic agents such as lodme to some of
the more complex agents such as antibioucs,
quaternary ammomum compounds and or-
ganic mercurials
Adhesive Tape Removers and Bandage
Adherents. The adhesive tape removers con-
sist of a solvent such as ethyl alcohol, ace-
tone or isopropyl mynstate, oleate, stearate
etc dissolved m the propellant Rosm, ben-
zom and other resmous matenals are used
for the bandage adherents The tape remov-
ers are useful m that they allow for the easy
removal of surgical tape with a mmimum of
imtation
Body Rubs. There are basically two types
of preparations used as body rubs One type
consists of a silicone incorporated mto a
suitable base, while the other consists of an
282 Aerosols
alcohol, such as ctbaaol or tsopropanol, and
a propellant. These products are generally
used for the prevenuon of bedsores m bed-
ridden patients
Bum remedies consist chiefly of a local
anesthetic m combmaiion v.ith antiseptic
agents such as sulfur, hexachlorophene, l^n-
z)l alcohol, tannic acid etc. In addition, cool-
ing and soothing agents such as menthol and
chlorobutanol ore generally present A ^^ 1 -
cal bum formulation follovss *
Oenzocame
1 00%
Camphor
010%
Menthol
010%
Pynlamme maleale
0 25%
Hexachlorophene
002%
Acetulan*
1 00%
Oleyl alcohol
4 00%
Dipropylene glycol
100%
Propellant lS2a/ll
92J3%
The eilccuvcncss of an anubiouc spray
powder m the local treatment of bums has
been noted by Games et al **
Dermatologic t'roducts. This is a rather
broad classificatioo and includes those prod-
ucts used as antipruntjcs, anu mQammatory
agents, in the treatment of acne or poison ivy
and related conditions etc Many of these
preparations utilize a steroid— generally cor
tisone or one of its dcnvativcs — as the them
pcutically actnc ingredient Other products
make use of antihistammics These products
arc ciitrcmcly cffccuvc, smcc they allow for
maximum penetration of the aciisc mgrcdi-
cntswithamimmumofwastc In most eases,
a thm him of medication is applied over the
affected areas, and in the case of foam prep-
arations. the medication is applied only to
the aUcctcd area without waste Several
studies indicating the ehectivcncss of many
dihcrcnt dermatologic aerosols have been
reported M u
Foot Preparations. The aerosol method is
an ideal method for the application of foot
preparations. In the treatment of athletes
foot, shoes, stoclangs and affected areas can
be sprayed easily with medication. The usual
mgrcdicnts for athletes foot remedies arc
undecylenic aad and one of its salts (such
os zinc undecylenate) although many other
mgrcdicnts are bemg used. Other foot prep-
arations male use of a talcum powder with
* Aaencan Cbolcsurot ProJucu.
or without an antiseptic agent such as bexa-
dilorophcnc
Spraj-OD Protective Films. One of the first
formulations for a spray-on protective film
utilized polyvinyl pyrrohdone and vinyl ace-
tate copolymers ^
PVP/VA (40 60) 100% solids 5 0%
PoIyeihylcDe glycol 600 0 2%
Ethanol, aohyd 24 8%
Propellant 142b/ 114 (30 70) 700%
Many mcdicmal agents such as antibiotics
and antiseptics can 1^ incorporated with this
basic formulation On application, the sol-
vent and the propellants vaporize, leavmg
behind a thm transparent film, whidi, m ad-
dition to providing protection, allows for the
visual inspection of the affected area Smee
this is a breathmg film,” the possibility of
infection by anaerobic bactena is minimized
Other protective preparations utilize a sili-
cone which provides a water-resistant film
over the affected area
Vitamm Preparations. Several multiple-
vitamin preparations have been formulated
using a compressed gas system** The pres-
ence of nitrogen ensures increased stabihty,
since many of the vitamins and the mmerals
present arc sensitive to oxidation However,
the viscosity of the product offers a serious
problem to the formidator Generally, a syrup
base IS utilized m order to mask the taste
of the vitamins as well as to ensure vitanim
stability Attempts have been made to pre-
pare metered vitamin preparations with vaxy-
ing degrees of success
Pbansacculicai Jahahals. The vapor Xnun
an inhalant type product is designed to give
prompt relief from the symptoms of nasal
and bronchial congestion Generally, the
vapors of therapeutically active ingrc^cnts
are produced through the utilization of a
vaporizer (see Chap 1 1 } Recently, aerosol
products have become available for this pur-
pose In use, an enclosed area is sprayed
with the mcdicmal ingredients The force of
the liquefied gas propellant disperses the
medicinal agents throughout the area m the
manner of a vaporizer In addition, these
products can be used to spray a small amount
of the mcdicmal on a handkerchief and the
vapors are then inhaled.
A typical formulation may contain the
following *
Medional Aerosols 283
Tnethylene glycol
03%
Dipiopylcne glycol
0 5%
Deltyl Extra
0 2%
S DA- Ethanol No 40
15 0%
Aromatic Oil
1 0%
Propellant 11/12 (50 50)
83 0%
Other Applications. Many reports have
indicated vanety of pharmaceutical
products 'which can be dispensed m aerosol
form.® 80 53 ei 63 i^ese products include
eye, car, nose, throat and dental preparations
Many of these products are currently under
investigation and in vanous stages of de
velopment However, problems as to foimu
lation, valve design, necessary applicators
etc must be solved before they can become
commercially available
MEDICINAL AEROSOLS
Inhalation therapy may be defined as the
admmistration via the respiratoiy system of
medicinal agents which are m ^e fonn of
fine solid particles or liquid mists In recent
tunes, physicians have administered pern
cUlm and other antibioucs by way of the
respiratory tract. Many drugs have been ad-
ministered by this method as mdicated by
Dautrebande,^* ^® Amsier,® Grant,®* Sul-
senti^® and Sciarra ** Neuroth*® discussed the
use of several devices suitable for the pro-
duction of aerosol particles
In 1955, the fint aerosol medicmal prod-
uct was mtroduced m the Umted States This
preparation consisted of a self-contained
pressurized umt which utilized epinephrine
as the therapeutically active agent In use,
the product dispensed finely subdivided par-
ticles of epinephrine The particles were m
the range of 10 microns and below, with 90
to 99 per cent less than 5 microns Accord-
ing to Dautrebande, for true mhalation ther-
apy the particles must be well below 0 5 mi-
crons and, in many mstances, of submicronic
size
In order to understand fully the therapeu-
tic efiBciency of inhalation therapy, a review
of the respiratory system is desirable How-
ever, a detailed discussion of this subject is
not withm the scope of this chapter Those
parts of the respiratory system to which m-
balation therapy is applicable have been re-
viewed by Sciarra and Lynch®* and are illus-
sirated m Figure 125
Since It IS known that the particle size of
therapeutic aerosols afiects their clmical use-
fulness, many mvestigations have been car-
ried out to determine the particle size that is
most effective for a given therapy Particle
sl~^ determmes the site of deposition m the
luugs and, hence, chmeal effectiveness Ac
cording to Abramson®^ and Fmdeisen,*® par-
ticles larger than 30 microns were deposited
in the trachea, those 10 to 30 microns m
size reached the terminal bronchiole, those
ranging from 3 to 10 microns reached the
284 Aerosols
Table 4S Particle Site op Isoproterenol and Episephrive Aerosol Suspensions
Mass Median
Diameter,* (microns)
Mass of Particles wttu
Diameters
<5 microns, ‘o
< 7 microns, %
< 10 microns, ^
Lot No
1 (Iso)
35
70
88
98
Lot No
2. (Iso)
27
78
92
99
Lot No
3 (Iso)
29
77
92
99
Lot No
4 (Epi)
3.5
73
93
100
*As determined by the "light scatter decay method** (analysis of the change m light intensity of a
Tyndall beam as an aerosol settles under turbulent conditions) From Ponish, L, et al Pressurized
pharmaceutical aerosols for tnhalaUon therapy. J Am Phann. A (Sci ) 71, I960
Table 49 Effect op Internal Pressure op Isoproterenol Suspension on
Particle Size Distribution Emitted
Pressure
(psis)
MMD
(microns)
Mass With Diameters
< 5 microns,
> < 7 microns, ‘e
' < 10 microns,
Sample A.
80
I 9
996
100 0
1000
45
37
690
89 0
98 6
Sample B
SO
ZS
83 (
95 4
99 6
45
40
66 2
89 0
98 9
FromPonish.L ftet J Am Phann A.(Scl)V9 7l 1960
als color duct, uhilc those panicles m the
range oM to 3 microns reached the alveolar
saes It has been funher reported that par*
tides less than 0 5 microns in size reamed
the alveolar sacs and were expired Other
workers have reported difTcrcnl values Also,
the per cent rcicniton of the pantclcs must
be considered LandahP** ** reported that
f iamdcs of 60 microns or more \tcrc col-
acted in the trachea with less than one per
cent for partidcs less than 6 microns Par-
ticles larger than 20 microns failed lo reach
the terminal bronchiole, while those larger
than 6 microns failed to reach the alveolar
duct Those panicles less than 2 mterons
faded to reach the region of the alveolar sacs
However, It IS more or less agreed in regard
to material to be deposited in the aivcoh for
therapeutic value, that those panicles less
than 0 5 microns must be considered. The
importance of particle size m aerosol therapy
has been indicated by Lovejoy
Freedman,-* Grater and Shucy,” Hams,**
SdUcr ’ and Zohman and Wdliams** all rc-
poned significant therapeutic improvements
when patients sulfcrtng from chrome asthma
were treated with liquefied gas aerosols con-
taming eiilier cpinepbnnc or isoprotcicnd
In a study of the cITccts of various nose drops
and sprays on vasomotor rhinites of preg-
nancy, It was found by Banon* that a Itquc-
fled gas aerosol containing phenylephrine
seemed to be the most cliccuvc agent The
author concluded that the beneficial results
obtained from this product were due to the
cRicicnt method of propelling the medication
into the nasal and the nasopharyngeal spaces
Administration of crgotaminc in the form of
a liquefied gas aerosol has been shown by
various investigators such as Finch,** Ryan,®*
and Speed** to be an effective and efficient
way of introducing the drug into the cir-
culation
Many medicinal agents lend themselves to
admimstration by inhalation In fact, a drug
given by intravenous injection can, in most
eases, be reformulated into a suitable aerosol,
provided that the drug is capable of being
deposited m the respiratory tract and is non-
irritaUng Such drugs as epinephrine, iso-
proterenol, octyl nitrite, phenylephrine and
ergotanune have been succcssfuly formulated
into liquefied gas acrosob The particle sizes
of isoproterenol and cpinephrme produced
by liquefied gas aerosols have been investi-
gated by Ponish et al“ and some typical
Veterinary Aerosol Products 285
results are given m Table 48 Table 49 illus-
trates the relationship between internal pres-
sure and particle size These products have
met with a great deal of success and have
been readily accepted by both phjsician and
patient
Some typical formulations of medicinal
aerosols follow ”
Angina Spray
Octyl nitnte
1 00%
Propellant 12/114
99 00%
Asthma Spray
Isoproterenol hydrochloride
025%
Ascorbic acid
0 10%
Ethanol
35 75%
Propellant 12/114
as
Asthma Spray
Epioephnne
0 25%
Hydrochlonc acid 3/V
050%
Ascorbic acid
015%
Water
100%
Ethanol, absolute
33 10%
Propellant 12
25 00%
Propellant 114
4000%
Figure !26 illustrates the package of a
medicmal aerosol which is available
VETERINARY AEROSOL PRODUCTS
Aerosol products offer many advantages
to the vetermary field In addition to ^e
generally accepted advantages of aerosol
products, vetennaiy aerosols (1) provide
mcreased penetration of medicuial agent
through the animals fur, (2) facilitate ad-
mmistration of the medicinal agent and (3)
minimizes loss of medication from the
aEccted area through activity of the animal,
smee the mgredieots are finely dispersed
Veterinary products have been developed
for use as deodorants, repellants, grooming
agents, antiseptics and germicides, and for
the treatment of several specific conditions
such as pmkc)e, mastitis, foot rot and ring-
worm Many of the pharmaceutical aerosols
previously covered are applicable to veteri-
nary use, however, only those products de-
veloped specifically for vetennaiy use wnD
be mcluded m this section
Antiseptic and Germicidal Vetennary
Aerosol Products. These products are m-
tended for the treatment of a vanety of con-
ditions from a simple wound or abrasion to
Fic 126 Schematic view of Medi
balei' showing valve assembly (Riker
Laboratones, Inc )
foot rot and nngworm The active ingredients
generally consist of antibiotics and antiseptic
and gennicidal ingredients A rather recent
development — an aerosol product intended
for the treatment of mastitis — consists of the
follovsmg ingredients per dose
Dihydrostrcptomycin
Neomycin
PoJymyxm B
Methylparaben
Propylparaben
Mill miscible vehicle to
250 mg
100 mg
71 000 Units
5 mg
1 25 mg
2.5 ml
The active ingredients are added to the
milk miscible vehicle and, after packaging,
the product is charged with mtrous oxide By
means of a metered valve, a measured dose
of 2 5 ml is dispensed through a special teat
tutw In use, the teat tube is inserted into
the teat canal The valve is actuated by press-
ing down and allowing the mcdicauon to flow
through
286 Aerosols
SPECIAL TESTING OF AEROSOL
PRODUCTS
Like other pharmaceutical and medicinal
products, aerosol products of a medicinal
nature require a “new drug” application
Mauser^* has discussed some of the data
which are necessary
The various components used to package
aerosol products must be thorou^Iy in*
spccted by the quahty control department
In addition to the genera! analytic control
procedures used m the manufacture of non-
aerosol products, several special tests are
required for aerosol products
A stringent requirement of the Interstate
Commerce Commission is that all aerosol
products pass a flame extension test” — that
IS, when the aerosol product is sprayed to-
ward an open flame, the flame must not ex-
tend more than a given length In Figure 127,
Fio 127 Flame cxlemioo test (Albed Cbcnucil Corp General Chemical Div )
An aerosol preparation suitable for treat-
mcot of pinkeye m cattle and sheep contains
Methyl violet
006%
Furfuryl alcohol
060%
Tetrahydrofurfuryi alcohol
0 03%
Urea
060%
Isopropanol
14 60%
Propylene ^ycol
9 11%
Propellant 12
37J0%
Propellant 1 1
37J0%
A typical flea, lice, and tick
conlam the following
spray may
Pyrethnns
006%
Pipcronyl butoxide
048%
Malathion
050%
Melhoxychlor
2,2 Thiobis (4 chloro-6 methyl
050%
phenol)
010%
Petroleum distdlate
23 36%
Methylene chlonde
1000%
Propellant 1 1
27 50%
Propellant 12
37^0%
References 287
a typical aerosol preparation is subjected to
this test. Additional tests are required to de-
termine the explosiveness of the product
usmg the “open” or the “closed” dnim ap-
paratus. The vapor pressure of the final prod-
uct must also be determined. It has previously
been mdicated that all aerosols are heated
to 130° F- in order to test for leaks and
strength of container. In the case of pharma-
ceuticals and medicmals, an exemption from
this test IS permitted for those products which
will undergo decomposition at this tempera-
ture. Many of these tests are desenbed in
detail m a publication of the Chemical Spe-
cialties Manufacturers Association,*
For spray products, the spray pattern
is extremely important. The application for
which the product is intended detenmoe
the requirements of the spray. The spraying
characteristics are dependent on the nature
of the fotmulaUon, the pressure and the
amount of propellant present, as well as on
the valve and the actuator. In many instances,
faulty manufacturing procedures can be de-
tected through an examination of the spray
pattern. Some contract fillers routinely ot^
serve the spray pattern of each aerosol con-
tainer produced. A typical spray pattern can
be seen in Figure 128.
These arc only a few of the necessary tests.
The entire filling operation for pharmaceu-
tical and medicinal aerosols should be closely
supervised. Mason and Hait*^ discuss some
of the difierences In fillmg and control pro-
cedures between pharmaceutical and non-
phaimaceutical aerosol products.
Pharmaceutical and medicmal aerosols
have established themselves as a dosage form
which has many unique features and a tech-
nology of its own. Smee this is a relatively
new dosage form and requires the use of a
liquefied or compressed gas, studies must be
initiated to determine the behavior of many
medicmal agents in contact with the pro-
pellants. hi addition, the pharmacolo^ ac-
tivity must be determined for both new and
old drugs, since the mode of administra-
tion is d^erent. As this mfonnatlon be-
romes available, it will be possible to
utilize aerosols more extensively as a dosage
form.
Fio. 128, Tbe spray pattern.
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59 Sanders, P A Non aqueous aerosol
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60 The Reaction of Tnchloromono-
fluoromethane with Ethyl Alcohol, Proc
C S M A 46th Mid Year Meeting, p 66,
1960
61 Scbenng s Dilodeim foam aerosol. Aerosol
Aged 27, I960
62 Sciaira, J J Development of phannaceu
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States, Aerosol Age 6 65, 1961
63 — — Aerosols and the pharmacist, J
Am Pharm Ass (Pract ) 19 672, 1958
64 Aerosol therapy, Aerosol Age
1 14, 1956
65 . — .... The Formulation of Self Agitating
Pressurized Food Products, Institute of
Food Technologists, 21st Annual Meeting
N Y,1961
66 The importance of aerosol lech
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Aerosol Age 4 66, 1959
67 Sciarra 1 1 , and Cestan, J E. Extern
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68 Sciarra, 3 J , and Eiscn, H Dermato-
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69 Sciarra, J J , and Lynch, V Aerosol in-
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70 Sciarra, J J , and Turney, F J Solubility
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72 Seltzer, A- A useful device for treating
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77 Sulsenti, G Cortisooic agents by aerosol
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80 Walker, M H A hydrocortisone panto-
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C/iapfer 9
Incompafibility and the
Incompatibilities of Inorganic
Compounds
Louis W. Busse, Ph D.*
The term incompatible or incompatibSity
Mihea applied to the nuung of mcdicanicnts
IS used most often to describe (1 ) the com*
bining of ph)$ically mconipatiblc substances
such as oil and v.aicr in the absence of an
emubificr, (2) Uie combining of substances
that will react chemically to form a com*
pound that is not desired, (3) the combming
of substances tint uiU react chemically to
form a more potent or toxic compound that
uill be m oserdose These types of tneom*
paubiliiy generally are classed as (1) physi*
col, (2) chemical and (3) Uierapcuiic
The study of prescription incompatibiliucs
requires the application of the knowledge
gained in all of the areas of the pharmacy
curriculum (i c , chemistry, physics, pharma-
cology and pharmacy) to the particular prob-
lem at hand A proficient pharmacist should
be able to anticipate the incompatibility
before mixing and know bow to treat it or
present it from occurring m order to dispense
the prescription
THER/\PELrnC INCOMPATIBILITY
In this kind of incompatibility, the most
frequent occasions where Uie consideration
of tile pharmacist is necessary ansc either as
matters of oicrdosage or the wnling for a
substance when somethmg else is mtended,
eg, mcrcunc chloride for mercurous, or
• Profestor of PtaimAcy, Umveojiy of Wo-
coouo.
barium sulfide for banum sulfate Since pre-
scnbing is the prerogative of the physician,
the occurrence of antagonistic combinations
such as stimulants and depressants, antispas-
modics and drugs which increase the lone,
cathartics and astringents, is of no concern
to the pharmacist unless the combmations
arc of such dosage as to be dangerous
Oterdosage m prcscnptions is considered
as a therapeutic mcompaiibility and may
occur frequently In evaluating dosage, the
student should always consider (1) the fre-
quency with which the drug is administered
and (2) the possibility of the combination
of drugs prescribed possessing a synergisiic
acUom Therefore, epmephrme and cocaine,
codeine and aspiim, meicunals and salicyl-
ates should be administered m smaller doses
in combination than when administered on
an individual basis
In many instances, the amount of the drug
administered m one day, if it possesses a
cuiDulativc effect, is as important a con-
sideration as the amount taken in each dose
The judging of the limits of dosage which
one would ^ow on a prescription is not sub
ject to method For the most part, this knowl-
edge will be acquired through experience and
ol»crvauon under the supervision of a phar-
macisL For the beginner, the simple rule of
not permuting any dose twice that of the
ofTictal average is a safe one Exception
might be made in the eases of such highly
potent drugs administered m doses less than
He© gr
290
Chemical Incompatibility 291
The student also should keep m mmd that
overdose can occur in prescriptions adminis-
tered externally as well as internally Thns,
m addition to Imowmg the doses of the potent
drugs administered mtemally, he must also
know the permissible concentrations of drugs
to be applied externally or locally when in-
corporated m the vanous vehicles and ap
plied to different membranes Permissible
concentrations of several drugs m various
type vehicles for application to cutaneous
membranes are given m Table 50
PHYSICAL INCOMPATIBILmr
The term physical incompatibility, very
frequently caUed pharmaceutical, is used to
descnbe those combmations or mixtures m
wtuch, the mcompaUbvUty is due to the lack
of solubility of one or more of the sub-
stances m the liquids of the prescription, or
the liquefaction of powders when triturated
together (m which case these are called
eutectic* mixtures)
Hie common examples of physical mcom-
patibility are listed below
1 Immiscible liquids— cmulsificauon neces-
sary
A Oil water
B Chloroform water
C. Balsams, etc water
2 Cementation of ingredients m mutures
A. Bismuth subnitrate plus acacia as a
suspending agent
B Zmc oxide and starch plus acacia as
a suspending agent
3 Precipitation because of decreased solu
bility
A. Alcoholic extracts plus water
B Hydrophilic colloids m a dehydrat
tng medium
a. Mucilaginous and albuminous
solutions plus alcohol
b Mucilaginous and albuminous
solutions plus electrolytes
(Hofmeister senes)
C Saturated solutions of volatile oib
in water plus salts
a Aromatic waten plus salts
* The term eutecuc is applied to the nuxiore of
two or more substances in such proportions that u
has the lowest melung point possible with those
cotnponenu iB pharmacy it generally is applied
to the mixtures of sohds hquuy at rooia.
temperature.
Table 50 pERxnssiBLE Concentrations
OP Drugs in Various Vehicles for
APPLICATION TO Cutaneous Membranes
Vehicle
Water
and/or
Alcohol
G/jcerin
Oily
Phenol 1-2%
5-6%
10%
Salicylic acid 1-2%
10%
Mercunc cUonde 0 0 1-0 1 %
1-2%
Anunomaled mercury 1-2%
10%
D Concentrated solutions of salts in
water plus alcohol
a Potassium citrate solution plus
hyoscyamus tincture
E. Supersaturated solutions at lowered
lempetatuics
4 Lique/achoa of sohd tagredients oa mixing
A Camphor and menthol
B Phenol and salol
C Camphor and chloral hydrate
An analysis of the above examples indi-
cates the necessity for broad general knowl-
edge m the following techmes or methods
if incompatibihues of this nature are to be
prevented or remedied
1 Emulsifying agents and technics
2 Suspenihng agents and technics
3 General knowledge of solubilities, solvents
and solvent action
4 The use of adsorbing agents (eutectics)
CHEMICAL incompatibility
Chemical incompatibihty is said to be
present if undesirable chemical reactions
occur or may occur on compounding (nux-
ing) of the medicaments tLs may be evi-
denced m numerous ways
I Precipitation
a By hydrolysis — zinc chloride m puri-
fied water, sodium phcnobarbital in
purified water
b By double decomposition— strontium
bromide plus sodium salicylate
Z Evolution of a gas
a. ^fcrvcscccice*“4iberaUQn of carbon
dioxide
b liberation of nitrous oxides
3 Color formation
292 Incompalibili^ and the Incompotibifities of fnorgonic Compounds
Table 51 Solubility of Salts in Water
Sparingly Soluble Soluble
Bromides, chlorides and Ammonium, potas*
iodides of lead, mcr- sium and s^ium
cury and silver salts
Great tact, diplomacy and sympathetic
understanding arc required at all times oa
the part of the pharmacist.
INCOMPATIBILITIES OF
INORGANIC COMPOUNDS
SulSdcs of all metals
except the alkaline
earth and alkali
metals which are sol-
uble UNH^)oS,Na.S.
CaS, BaS]
Sulfates and chromates
of banum, lead, mer-
cury, silver and stron-
tium
Hydroxides, oxides, car-
bonates, phosphates,
oxalates and carbon-
ates of all metals, ex-
cept the aUaH metals
and the ammonium
ion (NH«)
Chlorides, except
silver chloride,
mercurous chlo-
nde and certain
oxychlorides (zinc
oxychloride)
Acetates, nitrates
andnitntcs
a. Antipyrine plus ethyl nitrite (blue
color)
b Cherry syrup plus alkalis (change of
color)
c Ubecation of iodine from iodides tn
acid medium
Certain chemical cornbinaUoos, such as a
mixture of oxtdinng and ccducuig agents, at
times may be prescribed Tlicy arc not in-
compatible m the sense that they cannot be
dispensed However, dispensing of such com-
bmations may require particular care and
skill m the order and the method of mixing
and handling
The decision as to whether die product of
a chemical reaction which occurred dunng
the mixing of the ingredients is undesirable
again cannot be based on general considera-
tions Each prcscnption presents an individ-
ual problem, particularly when a different
physician is involved each time. The limits
to which a pharmacist can go in changing a
prescription according to his best judgment
mvolvc the physiciaii pharmacist relation-
ship KnovvJcugc and txinfidcncc in the judg-
ment of the pharmacist con be built up m the
physician only by long and saiisfacio^ expe-
rience with the pharmacist and his work
In the discussion m this chapter, the ob-
jective IS to survey the chemici incompati-
bilities which may occur as a consequence
of solidnlity differences The substances are
grouped into inorganic (accordmg to occur-
rence m the periodic table) and orgamc com-
pounds While the morgamc compounds can
be considered on the basis of thetc anion or
cation components, the periodic grouping
seems to lend itself to a more coherent dis-
cussion and to lead to less repetition Gen-
eral solubility rules precede each discussion
General Solubility Rules
This discussion is directed primarily to-
ward the solubility or insolubility of these
substances m water or dilute concentrations
of alcohol and water
While there are numerous exceptions to
solubility rules, the following may be stated
for their usefulness m predicting solubilities
ID prescription combinations
1 Inorganic compounds m general tend
to dissolve in water (polar), while organic
compounds tend to show insolubility m this
solvent
2 Inorganic compounds m general arc
quite insoluble m organic solvents (nonpolar)
such as benzene, cilier and chloroform
3 Acids, bases and salts (ionic and polar
compounds) will be more soluble m a polar
solvent (water) than m a solvent such as
benzene
4 Orgamc compounds (nonpolar) will be
more soluble in the nonpolar solvents
5 Salts with weak crystd forces and high
tendency to hydrate will be water-soluble
6 Salts with strong crystal forces and
sU^t tendency to hydrate will be sparmgty
soluble in water
7 Salts formed from univalent ions which
arc easily hydrated and have relatively weak
coulombic forces between the ions arc usu-
ally soluble
8 Many salts formed from combmations
Incompatibilitiej of Inorganic Compounds 293
Table 52 Souibility of Salts op -niE
Alkali Metals
Salt
Solubility
Gm /100 ml.
Polassjum nitrate
3} 6
Potassium chlonde
34 0
Potassium sulfate
it li
Potassium phosphate
SI sol
Sodium nitrate
87 5
Sodium chlonde
35 8
Sodium sulfate
18 89
Sodium phosphate
11 11
Lithium chlonde
78
Lithium nitrate
71 45
Lithium sulfate
35 0
Lithium phosphate
0 039
Ammonium nitrate
192 4
Ammonium chlonde
37 0
Ammonium sulfate
76 0
of a divalent or tnvaleot ion and two or three
univalent ions are quite soluble The poly*
valent cations are usually highly hydrated
because of a large central charge This high
degree of hydration counteracts the mcreased
coulombic forces between the polyvalent
cation and the univalent anion
9 Almost all salts formed from combina-
tions m which both ions are polyvalent (di-
valent, tnvalent or tetrava/ent) arc spar-
mgly soluble m water
Table 51 illustrates some of the general
solubility rules for morgamc salts
Group I Alkali Metals
(U, Na, K,NHi+)
These cations, m general, form watef-
soluble salts with all the umvalent and the
divalent amons, Q, NO 3 (acids) Salts of
the tnvalent anions (PO*) will tend to be
much less soluble even to the point of being
slightly soluble Tabic 52 illustrates this fact
The data m Table 52 indicate that, m
general, aromooium salts are more soluble
than lithium salts, lithium salts are more
soluble than sodium salts and sodium salts
arc more soluble than potassium salts The
cations of Group 1, then, appearmg m their
Table 53 Comparison op Energy of Hy-
dration OF Alkali Ions with the Solu-
bility OF Their Chlorides and Sulfates
U+
Na+
K+
Hydration energy
(Kg Cal /Gm.
mole ion)
136
114
94
Solubility of chlondes
(Gm/lOOmI)
78 0
35 8
34 0
Solubility of sulfates
(Ghl/IOO ml )
35 0
18 89
11 11
order of decreasmg solubility, are NH 4 +,
U+.Na+,K+
With the cKception of the ammomum ion,
these differences m solubilities can be ex-
plained on the basis of the difference m
the energies of hydration* of these 10 ns See
Table 53
These deductions or correlations are sub-
stantiated further by the work of Buchner'
and CO workers, who measured the salting*
out effect of these ions and established the
lyotropic numbers These numbers for lith*
lum, sodium and potassium are given m
Table 54 Since the lyotropic number is
directly related to lomc hydration, these data
also lend support to the general solubility
statements made regarding these cation salts
These differences m solubilities also con
be rationalized and explained on the basis
of the ionic radius of these lOns The degree
of hydration is, in a maimer, a measure of
the solubilizing properties of these 10 ns and
IS related to the intensity of the electro-
static field surrounding the ions Thus, m 10 ns
having the same valence, the smaller ions
(smaller ionic radius) have a more mtense
“ Energy of hydration Is defined as that energy
nbich IS released i^hen lOos luually in a vacuum
are placed la pure water These figures indicate the
relative aflinity of these ions for water
Table 54 Lyotropic Numbers of Alkali
Ions
Cation
Lyotropic
Number
U+
115
Na+
100
K+
75
294 Incompatibility and the Incompatibilities of Inorganic Compounds
Table 55 Relationship of Electrostatic
Fields of Alkali Cations to the
Solubility of Their Salts
Ll+
Na+
K+
Ionic radius
(Angstrom units)
0 60
0 95
1 33
Rauo of charge to
radius
167
1 OS
075
Solubility of bromides
(Gm /lOO ml )
177 0
90 24
652
field than the larger tons and, therefore,
greater hjdration energy This relationship
IS illustrated m Table 55
The fact that these ions do form water-
soluble salts IS evidence that these univalent
cations are not the cause of many incom-
patibilities m themselves The majority of
the mcompattbilitics are caused by the anion
component of the salt
In addition to the general mfonsatioo re-
garding these cations, the folloumg specific
facts should be learned
1 Lithium salts (Cl, I, Dr) are often del-
iquescent and are freely soluble m alcohol
and glycerin Their solubility m alcohol is
much greater than that of the correspondmg
sodium and potassium salts
2 \Vhen these cations arc corabmed with
anions from weak acids, they form salts, the
aqueous solutions of which are alkaline m
reaction This rcsuliuig alkalmity is Cre-
quenily the cause of the precipitation of the
free alkaloid from alkaloidal s^ts which gen-
erally require an acid pH for stabibty
3 Ammonium sales will decompose with
the liberation of ammoma in strongly alka-
line solutions The rate of decomposition is
mcrcascd with increasing temperature
Group 2 The Alijvline Earth Metals
(Barium, Strontium, Calcium and Mag-
nesium, AND THE Heavy Metals Zinc and
Mercury)
The Alkahne Earth Metals
The cations Sr++, Ca++ and
Mg++, like Li+, Na+ and K+, will form
water-soluble salts with the univalent anions
(F-,Cl-,Br-,I-,NOj“) \Vhcncombmcd
Viiih divalent and tnvaicnt anions (S 04 "“,
Table 56 Comparison of Hydration En-
ergy AND Solubilities of the Hydroxides
OF THE Alkaline Earth Metals
Ba
Sr
Ca
Uq
Atomic weight
137
87
40
24
Hydration
energy
346
376
410
490
SiMubiljty
Gm /lOO ml
3 89
0 77
017
0 001
moles/Iiter
0 233
0 066
0 022
0 0003
COi — , PO* ) the resulting salts are,
for the most part, msoluble m water
Exceptions to the univalent anion solu-
biliQr rule arc the bicarbonate and the hy-
droxide compounds which arc msoluble The
solubility of the bicarbonate salts of the alka-
line earth metals (divalent) is generally
greater than that of the carbonate com-
pounds The reverse is true m the alkali metal
group of cations where the carbonate salts
arc more soluble than the bicarbonate
The hydroxides of the alkaline earth
metals arc, in a pharmaceutical sense, quite
insoluble These do not follow the solubility
order when based on the energies of hydra-
tion of the cation Table 56 illustrates thu
reverse order
With the exception of the hydroxides, the
order of solubility of these cations follows
quite closely the rules set forth under Group
I According to their energies of hydration,
the salts of magnesium should be more solu-
ble than those of calcium, calcium salts more
soluble than strontium salts and strontium
salts more soluble than banum salts Table
57 shows this relationship to be true, with
the exception of the magnesium salts These
arc less soluble than the calcium salts, with
the exception of the sulfate anion. Magne-
sium sulfate IS very soluble
Tlius, even m the solid state, magnesium
sulfate is largely hydrated and, therefore, the
further separation of the ions on going into
solution IS an easy process However, as the
size of the positive ion (Ba++) approaches
the size of the anion, we have a compound
whose ions arc approximately equal m size
The barium ions will pack quite firmly into a
solid crystal and, therefore, it is not necessary
for water to fill up the crystal lattice The
bttcr may even be prevented from happen-
Incompatibilities of Inorganic Compounds 295
Table 57 Solubilities op Salt$ of the Alkaline Earth Metals
Barium
SntoNnuM
Calcium
Magnesium
Atomic weight
137
87
40
24
Hydration energy
346
376
410
490
Fluorides
Gm /lOO ml
016
0012
0 0016
0 00076
Chlorides
Gm /lOO ml
35 7
529
74 5
54 S
Gol Mol /lOOml
0 333
0 67
0 576
Bromides
Gm noo ltd
101
102
96
96 5
Gm Moi /100ml
041
2 08
1 91
Iodides
Gm/lOOmJ
203
177 8
2D0
148
Gm Mol /lOOml
051
0 68
0 53
Nitrates
Gm /lOO ml
93
608
121 8
73 2
Gm MoL/lOOmI
028
074
0 49
Sulfates
Gm /lOO ml
0 00023
001
02
34 4
ug When this occurs, a very insoluble sub*
stance voU be the result
All of the salts of these cations which
contain a univalent anion (Cl', Br', I”,
QOa”, NOj") are deliquescent and fona
highly hydrated salts They are also quite
soluble m alcohol, water and glycerin Their
deliquescent property necessitates their being
UghUy stoppered during storage penods
When dispensed as a powder, they very often
require the addition of an adsorbing agent
Tim deliquescent property is ch^cter-
istic of salts which are highly hydrated
and crystallize with several molecules of
water of crystallization, le, MgCljdH^O,
Caa2 6H2O, SrCl2 6H2O, MgSO* 7H2O and
CaS04 2H2O Of these 10ns, the Mg+'*’ ion
is generally the most highly hydrated This is
because it is the smallest ion of the senes
For example, in combmation with the larger
SO4 — ion it does not fill completely the
space bclvseen the sulfate ions with its own,
and there is room remaining for 7 molecules
of water around each magnesium ion This is
illustrated m Table 58
The mcompatibiliues of this group ap*
pear chiefly uhen these morganic salts are
placed m solution with uni*divalcnt salts or
v^ith salts of orgomc acids whereby double
decompostuon occurs Viith the formation of
a salt having 2 divalent components or a
di\ alcnt cation and organic amon
Caa2 + Na2S04 CaSO* | + 2NaCl
SrBr^ + 2Na Salicylale -» 2NaBr + Sr
Salicylate i
2NapheaobarbitaI + Ca(OH)2 -♦
Ca phenobarbital + 2NaOH
Salts of these alkalme earth cations with
moDOcarboxylic organic acids having more
than 4 carbons will for the most part be in-
soluble, except with those orgamc acids con-
taining sufficient hydroxy or ammo groups to
associate with water and solubilize the salts
Examples are levulenic acid, lactic acid,
glucomc acid and some ammo acids (such
as glutamic acid)
Physical mcompatibilitics frequently occur
with magnesium oxide because of its prop-
erties of hydration The hydration occurs
more rapidly and to a greater degree the
Table 58 Hydration, Solubility and
Ionic Size for Sulfates of Alkaline
Earth Metals
Ion
Radius
10-8
CM
H3O
LN
Solid
Solubility
Gm /IOO
ML.
SO4 —
15
Ba+ +
14
0
0 0002
Sr++
1 15
0
001
Ca+ +
1 0
2
02
Mg-t-+
0 65
7
27 0
296 Incompatibility ond the Incompohbiiities of inorganic Compounds
smaller the particle size of the oxide Thus,
light magnesium oxide should never be used
m hquid preparations, for, ^^1th a limited
amount of water, it sets to a cementhke hard-
ness The ‘ heavy” magnesium oxide (larger
particle size) is h)drated less easily and ab-
sorbs much less water and, therefore, is pre-
ferred to the “light"
When studying this group of cations, the
student should always keep m mmd the
toxicity of the barium salts Banum sulfate,
which is the only salt of banum commonly
used medicinally, is msoluble, thus preveot-
mg systemic absorption. The soluble banum
chloride is sometimes used medicmally to m-
creasc the ventncular rate in the Stokes-
Adams syndrome, however, this use is rare
For this purpose, it is admmistered m doses
of 30 to 40 mg 4 Umes daily for a day or
two until the attacks arc controlled Barium
IS a marked stimulant for all types of muscle
Zinc and Mercury
So far, we hate been able to explam the
solubility relationships of the cations m
Group 1 and 2 on the basis of hydration
energies, lyotropic numbers and the ratio of
the charge to the ionic radius This was pos-
sible because the bonding of all of the com-
pounds formed by these cations were, for the
most part, purely ionic in character As was
seen from the solubility diustrations, most of
these salts were quite soluble Since only the
possibility of ionization makes solution of an
ionic solid (Na+Cl") possible, one can rea-
son that the positive ion (Na*^) under the
existing coodiuons has a greater attraction
for the water molecule than for the chlondc
(Cl“) ion, for example This is true m the
case of the alkali metals and the alkalmc
earth metals In those insoluble salts, m
which the bonding is purely ionic (BaSO«,
CaCOs), ions of higher valence are mvoivcd
and the solubility then is dependent on the
rclau^c strengths of the ionic forces m the
oystal lattice
However, m the case of the transition
metals, the matter is much more m doubt. In
this group, it appears that the force between
the positive ions (Ag+) and chlorine
for example, is rclauvcly greater than that
between water and silver ion
This mdicatcs a tendency for the bond to
be partly covalent m nature, and a greater
importance of van dcr VVaaJs’ and dipolc-
dipole interaction forces in the formation of
these crystal lattices
Hydration. All of the cations exhibit an
attraction for water and this attraction m-
creases with the charge on the cations —
monovalent least and the tn- and tetravalent
the highest As the energy of hydration in-
creases [indirectly a measure of the attraction
of the cation (+) for oxygen (~) m water]
the bonding between the cation and oxygen
changes Thus, m the alkali and the alk^me
earth metals, for example, the water of hydra-
tion seems merely to occupy holes in the
crystal lattice (weakly bound), while m the
transitional and heavy metals the water ap-
pears to be deiimtcly attached to the specific
cation [Al(6H20)Cls] in many of the salts
It is the latter type of coordinate bonding
which IS a factor causing many of these diva-
lent and trivalcDt cation hydroxides to be
amphoteric in character
The principal amphotertc hydroxides arc
Zn(OH)2, So(OH)j, Pb(OH)3, (AIOH)#
andCr(OH)3 These hydroxides will dissolve
m an excess of alkali, fonnmg their respective
loosasfoliows
Zd(OH)4—
Sn(OH),-
Pb-(OH)3-
AJ(0H)4-
Cr(OH)4-
Zmeate ion
Stamiite ion
Plumbite ion
Aluimnate ion
Chromite ion
Zinc and mercury each forms a complete
senes of salts that (filler greatly m their solu-
bih^ m ivatcr In addition, mercuiy exists m
two states of oxidation and forms the two
senes of salts, mercurous (Hg+) and raer-
cunc (Hg++), which also differ as to solu-
bdity This relationship is shown in Tabic 59
From the data m Table 59 , one can read-
ily gather that even the more soluble mercury
s^ts arc less soluble than the corresponding
zinc salts and that there arc many more solu-
ble zme than mercury salts The soluble zinc
salts shown in Tabic 59 ore all hydrolyzed
readily The hydrolysis of zme salts produces
the cation Zn(Hj0)30H+ The ionic speaes
which exist m zme solutions of different pH
values arc as follows
Acidsolulion 2n(H20)4++
Zn(H20)j(OH) +
IncotnpQitbliities of Inorganic Compounds 297
Table 59 Solubility of Salts of Zinc and Mercury
Zinc Salt
Solubility
Gm /lOO ML.
Mercury
Salt
Solubility Gm /lOO ml
Mercurous Mercuric
Acetate
30
Acetate
0 75
25
Borate
Soluble
Fluonde
SS
Fluonde
Decomposes
Decomposes
Chlonde
432
Chlonde
0 00021
69
Bromide
447
Bromide
0000004
061
Iodide
437
Iodide
SS
SS
Nitrate 3 H 2 U
327
Nitrate
Decomposes
SS
Nitrate 6 H 2 O
184
Sulfate
865
Sulfate • 6 H^O
Soluble
Sulfate
0 06
Decomposes
Sulfate • 7 H 2 O
96 5
Sulfides
Insoluble
Sulfide
Insoluble
0 000001
Hydroxide
Insoluble
Hydroxide
Insoluble
Insoluble
Neutral solution Zn(H 20 ) 2 (OH) 2 Zn(OH)j
Zn(H20)(0H)j
Basic solution Zn(OH)4 — Zlincaie ion
According to Pauling,^ the conversioa of
each complex into the next occurs by removal
of a proton from one of the four water mole-
cules of the tetrahydrated zinc ion. The pre-
cipitate of zinc hydroxide is formed by loss
of water from the neutral complex
Za(HsO)j(OH)2
The hydrolysis of zinc chlonde, for ex-
ample, IS a partial one and may be illustrated
as follows
Zn+++Cl-+HOH5^
ZqOHCI (solid) +H+
The basic salt of zmc oxycWondc is formed
and will precipitate, giving a cloudy solution
The formation of HCl also mdicates the fact
that these salts are acidic m solution This
cfiTTiff type of reaction occurs with all of the
Tin e salts of the halides and the acetate The
nitrate and the sulfate do not hydrolyze
as readily and therefore form more stable
solutions
Zmc salts will readily form the msoloblc
hydroxides m neutral and shgjitly alkaline
media and precipitate according to the equa-
tion
Zn+ +SO 4 — + 2X+ OH- ^
OH
/
Zn
\
OH
+ X-SO4
These salts should be buffered when dis-
pensed as solutions m prescription practice
A common example is the formation of a
basic zmc borate in the alkaline medium of
sodium borate, with bone acid the true zinc
borate is formed and is soluble Very weak
solutions of the sulfate and the chlonde are
dispensed frequently as mild antiseptics and
astringents for use in the eye or the nose
Zmc salts wiU be precipitated also when
combmed wuh salts of orgamc acids of more
than 4 carbon atoms m solution An example
of this would be
C— OVa
I
ZnSO* + 2 i
/
c— o— Zn— O— C
I \
c c
OH ^C— OH i + Na^04
I II I II
c c c c
c c
In addition to precipitating the organic
acids, the salts also precipitate the larger
29B incompatibility and the Incompatibilities of Inorganic Compounds
molecules containing carboxyl groups, such
as acacia, proteins and tannins These they
precipitate not only by virtue of their fonn-
ing zinc salts but i^o by dehydration oi the
large hydrated molecule However, the de-
hydrating properties take place only when to
fairly concentrated solutions In addition,
the anions (SO^ — , C1-, etc ) play a great
part m the dehydration Therefore ZnS04,
for example, would be more dehydrating
than ZnClj since the SO4 — ion is higher in
the Hofmcisler senes than the Cl~ ion
(ZQSO4 w'lll precipitate methylccllulose sus-
pensions in this manner)
Frequently, the insoluble compounds of
zme arc desired, and such as the zinc sulfides
generally are precipitated freshly in order to
get the finest particle size
Potassa sulfurata + Zinc sulfate
Potassium sulfate + Zinc mono and polysulfides
This is an example of a chemical reaction m
a presenpuon which is not an mcompaubility
The oxides and the peroxides arc used fre-
quently as dusting powder for their mild
astrmgent, antiseptic and deodorizing prop-
erties
The zinc ion also readily forms complexes
such as Zn(HoO)4++, Zn(NHj)4++ and
Zn(CN)4++ Thcfonnatioao{Zn(OH)afiu
into this system of complex formation Ac-
corduig to Pauling,’ 2 molecules of
2hi(H20)3(0H)3 can combme with the loss
of water to form the larger complex,
H
HO O OH
/ \ / \
HjO O OH2
H
By contioumg this process, an mfimtcly long
chain could be formed
H H H H K
00000
/\ / \/ \/ \ /\
- Zn Zo Zn Zo —
\/\ / \ /\ /\ /
00000
H H H H H
The structure of Zn(OH)3 precipitated is
thought to be essentially this
Mercury forms two senes of compounds,
one of which has an oxidation state of -{-1
(mercurous) and one an oxidation state of
4-2 With the exception of mercurous chlo-
ride and mercurous oxide, the mercurous
salts are not used widely in pharmacy and
medicine This is due to the fact that they
are very msoluble and unstable chemically,
since they are easily reduced to metallic
mercury by the action of hght The mercur-
ous ion consists of two mercuric ions plus
twro electrons which form a covalent bond
between them [Hg Hg]++ Mercurous chlo-
nde then may be pictured as having the
linear covalent structure
Cl-Hg-Hfi-ci
This covalent structure contributes much to
the insolubility of these compounds
There are two factors one should always
keep in mind m dispensing the mercurous
salts (1) they are reduced easily, and this
IS hastened by light, moisture and tnturation,
(2) mercurous salts may form the more solu-
ble mercunc salts in the presence of excess
anion, thereby causmg imtation For ex-
ample, It has been reported that imtation
occurred when calomel was used as a dusung
powder m the eye at the same tune that
potassium iodide was being administered
mtemaUy The more soluble potassium mer-
cunc iodide was formed m the tissues be-
cause of the presence of the iodide ion
Simultaneous administration of soluble
halides and insoluble mercurous salts is con-
traindicated.
The mercunc salts (Hg++) possess dif-
ferent properties from the corresponding
compounds of zme These diUercnces may
be explained in part by the strong tendency
of the mercuric ion to form covalent bonds
These differences arc reflected m the low-
ered soIubiJj^ of the mercunc salts over those
of zinc This IS illustrated by the solubility
products of the sulfides.
Solubility
Salt Product (Kgp)
Zinc sulfide 10~-‘
Mercunc sulfide 10“®*
and by the much greater solubili^ of the
halides of zinc as illustrated m Table 59. The
Incompatibilities of inorganic Compounds 299
tendency toward a greater covalent character
m these compounds is substantiated also by
the difference m melting and boiling points
between the salts of mercury and zinc The
greater tendency for mercury to form cova-
lent bonds IS mdicated by its low boiling
pomt and meltmg point
The mercuric ion has a strong tendency
to hydrolyze and to precipitate basic salts
HgfNOala + HOH Hg
\
OH
+ HNOj
This tendency is mcreased m alkaline
medium.
Of the somewhat soluble salts, mercainc
chloride has the least tendency to hydrolyze
m solution because of its very low degree of
ionization and, therefore, its small concen-
tratton of mercuric ion The mercury ts pres-
ent mainly as un ionized Imear covalent
molecules
Cl— Hg— Cl
However, solutions of mercuric chloride are
stabilized by ammonium chloride, and, for
stock solutions, the addition of a small
amount of the latter is recommended
Mercuric iodide is one tenth as soluble as
mercuric chlonde but is solubilized in an
excess of iodide ion It forms a soluble com-
plex salt, potassium mercunc iodide, accord-
ing to the followmg equation
/
I I
/ / \k
Hg +2KI s^Hg ,
\ V'
\
The addmon of potassium iodide to solu-
tions in order to solubilize mercunc salts is
jusufiablc and aixording to the best art. How-
ever, these solutions liberate iodine slowly
on standing and turn jcUowish m color The
addition of a small amount of sodium thio-
sulfate IS recommended to keep the lodme
from colormg the solutions The dispensing
Table 60 Properties of Zlnc and
Mercury and Their Salts
KfETAL
AND Salt
BP
CC)
MP.
CO
Zinc
907
419
Mercury
356
-38 9
Zme chlonde
732
262
Mercunc chloride
302
276
of such combinations of mercunc salts as
will form potassium mercunc iodide with
alkaloids or solutions containing alkaloids is
to be avoided, smee this salt is an alkaloidal
preapitant t'^en used for this purpose m
analysis, it is known as Mayer’s reagent In
addition to alkaloids, mercunc salts also
precipitate proteins, orgamc acids of more
than 4 carbon atoms and tannms
The incompatibility of the mercury salts
may be summarized briefly as follows
1 Hydrolysis to basic mercunc salts
which are insoluble, particularly in the al-
kalme medium
2 Reduction to meialbc state m the pres-
ence of reduemg agents This is particularly
true of the oxides This reduction is hastened
by light and heat
3 Precipitation due to the formation of
an insoluble salt through double decompo-
sition
Groups Boron and Aluminum
The metalloid boron docs not occur in
the free state m nature In pharmacy, we use
It as the hydrated BaOj known as ^nc acid
(H 5 BO 3 ), or the complex borate mineral so-
dium tetraborate decahydrate (Na^B^Or*
10 H 2 O) called borax The mcompabbilities
of these substances are due not to the borate
ion as such but chiefly to the acid or basic
properties of the solution (Sec under the
met^s for the rcspccU>e mcompatibilitics )
Aiumuium is the only caUon from this
group that is of known importance to phar-
macy Of the aluDunum compounds, only the
chlonde, the sulfate, the phosphate and the
hydroxide are used frequently The double
sulfates of alummum with cither potassium
or ammomum (alums) arc used as styptics
(styptic pencils) mfrcquently, however, they
aic used m great quantities mdustnoUy to
300 Incompatibjlity and the Incompatibilities of Inorganic Compounds
Table 61 Hydratios Energies
Hydration Energy
Ion
(Ko Cal /Gm M ion)
A1 + + +
1,149
Fe+++
1,18S
produce the hydroxide for medicinal use and
as a mordant in the dyemg process
Aluminum is a member of the third penod
with all three valence electrons m the third
energy level and so is always trivalent
A 1 +- 1 -+ has a very small ionic radius and,
as a result, a very high electric intensity at
the surface This is manifested in a great at*
traction for water, resulting in a bi^ heat of
hydration and hydration energy In fact, of
the tons used m pharmacy and medicine, the
aluminum ion is second only to the feme
ion (Fe+++) m hydration energy
The lomc radius and the ratio of charge to
radius of socrol ions arc shown in Table 62
The very small lomc radius of + and
the high ratio of charge to radius explain why
this substance is never found free m nature
and why it forms the hydrate (H 3 BO 3 )
boric acid so easily
Because of its hydration energy, the alu*
mmum ion is always associated with 6 mole*
culcs of water in solution, and this mcreases
the tendency to form soluble salts, many of
them hydrates
The chief msolubic salts arc the carbonate
and the phosphate
Of the soluble salts of aluminum, the chlo-
ride and the sulfate are used most commonly
Both salts arc ionized m solution, and, since
they are the combmation of a weak base and
a strong acid, they confer an acid pH to the
medium They hydrolyze slightly in solution
and, therefore, should be stabilized with an
excess of anion— eg, alumuium chloride
with ammonium chlonde or aluminum
sulfate with ammomum sulfate
Aluminum chlonde is unique m that m
ihe anhydrous slate it is one of the few ex-
amples of an morgamc compound existing
as a molecule It is not in tlic fonu an
ionic solid It is stable and can be distilled
and sublimed. It hydrates very rapidly to
form the Al( 6 H 20 )CIj w-ilh great rapidity
and violence Caution must be used m ban-
Table62 Ionic Radius
Ion
Ionic Radius
(Angstrom
Units)
Ratio
Charge TO
Radius
Ba++
U5
1 48
Sr+ +
1 13
1 77
Ca+ +
0 99
2 02
Mg+ +
0 65
3 03
A1+++
050
60
B+ + +
0 20
150
dling the anhydrous compound In solution,
however, the type of bondmg changes, and,
in sufficient dilution, the salt appears to be
completely ionized
llie acidity of both the sulfate and the
chlonde in solution is quite high, and for use
on the shn these solutions should be buf-
fered Concentration of 10 per cent should
not be exceeded for general astringent usage
as an antiperspirant
Aluminum, hie zioc, will form basic salts
such as aluminum subacetate (Al(OH)
(CsHjOj) xHsO When dried, this salt is an
msoluble compound, but, if it is prepared and
left 10 solution, It will continue to be soluble
The salts are not very stable and hydrolyze
to form the msoluble hydroxide and precipi-
tate out
Aluminum hydroxide gel is a colloidal sus-
pension of A 1 ( 0 H )3 The colloidal suspen-
sion IS destroyed by heal, freezmg, electro-
lytes and dehydrating agents On drying, the
particle size mcreases rapidly, which greatly
reduces the adsorbing and reacting powers of
the compound Aluminum hydroxide is solu-
ble m t»th acid and alkali and so is am-
pbolcnc Like zinc hydroxide, it acts as an
acid and, therefore, will form alummate salts
Al(OH), + NaOH Na+AlOj + 2 H 2 O
The reaction is a typical neutralization, with
alummum hydroxide functioning as the acid
Group 4 Tin and Lead
Tin and lead have two elections m the Po
and Px levels and, therefore, exist m diflcrcat
valence stales which involve cither ( 1 ) loss
of ail four valence electrons Pb-*'+++, (2)
loss of only the Pj level electrons Pb++, (3)
gain of four electrons to give structure of the
succeeding rncit gas
Incompatibilihes of Inorganic Compounds 301
Table 63 Solubilities of Aluminum
Compounds
Aluminum
Salt
Solubility
(Gm /lOO ML )
Acetate
Soluble
Bromide anhydrous
Soluble with violence
Bromide • 6H2O
Soluble
Bromide • ISHjO
Soluble
Chlonde anhydrous
Soluble with violence
Chlonde • 6H2O
Soluble
Iodide anhydrous
Soluble with decomposi
tiOD
Iodide • 6H,0
Very soluble
Nitrate
63 7
Sulfate anhydrous
31 3
Sulfate •9H2O
Soluble
Sulfate • I8H2O
Soluble
ITie relative stability of the 2* and the 4+
valences in this group is m accord with the
general rule that the highest positive valence
in the families is more stable in the odd-
numbered periods Therefore, the 4+ valence
of tin m the fifth period and the 2* valence
of lead m the sixth period give the most
stable compounds In agreement with this
rule IS the fact that the plumbic (Pb++-++)
compounds ate relatively few in number and
quite unstable In pharmacy, therefore, we
are mterested chiefly m the plumbous
(Pb++) compounds of which acetate, arse-
nate, sulfate, oleatc and the monoxide are
used most frequently
Lead preparations are used primarily as
astnogents and act by virtue of the lead ion
reactmg with the proteins of the skin fonn-
mg an msoluble lead protcinate The degree
of astnogency is related to the degree of
ionization of the lead salt The very soluble
compoxmds are very astringent, while slightly
soluble compounds cause a mild astnngency
because of the slow release of the lead ton m
the tissues
Table 64 shows the soluble and the sh^tJy
soluble compounds of lead
Solutions of lead salts or suspensions of the
insoluble compounds almost always arc pre-
scribed as such, and, therefore, few mcom-
patibilities anse However, it should be kept
in mind that, with the exception of the sol-
uble salts shown m Table 64, all other lead
salts are insoluble, and, therefore, if other
Table 64 Solubilities op Lead
Compounds (Water to Dissolve
1 Gm )
Soluble
Acetate
1 6 ml
Nitrate
20
Subacetate
160
Chlonde
93 0
Bromide
200 0
Slightly Soluble
Iodide
1,350
Fluonde
1,600
Sulfate
2,225
Borate
IsBoluble
Arsenate
Insoluble
compounds were added to such solutions, an
incompatibility would be certam to result,
1 e , lead would be precipitated by acids,
sulfates, chlorides, citrates, carbonates, al-
kalis, tannis, phenols and plant extracts
(tinctures, fluidextracts, etc )
Very frequently, suspensions of finely sub-
divided insoluble lead salts are prepared
extemporaneously m preference to suspend-
mg the powered salt as such For example, a
frequently encountered prescription is
n
Zinc sulfate
Lead acetate, aa 0 300
Punfied water, q s 120 0
Sig Apply as directed
Such precipitates are not considered un-
desirable, and a similar illustration is en-
countered m lead and opium wash
Lead acetate 1 8
Opium tincture 3 5
Purified water, q s 100 0
Sig Apply as directed
In this case, the msoluble lead mecooate is
desired and serves as a mild astnngent sus-
pension
The more serious problem encountered
mth solutions of lead salts is stability The
chlonde, mtrate, acetate and subacetate are
all hydrolyzed m solution easily and react
quiclJy with the carbon dioxide in the water
and arc precipitated out as the basic lead
carbonate This is illustrated in the unstabihty
302 Incompatibility ond the Incompolibilihe* of Inorganic Compounds
of the oQIcial solutions of lead acetate and
subacctate Up to the present tune, no effec-
tive means of stabilizing these solutions has
been devised Precautions such as using
boiled water, which is carbon-dioxide free,
and keeping small completely filled bottles
to exclude air should be observed when pre-
parmg solutions of lead salts
Groups Arsenic, Antimony and
Bismutii
Arsenic, antimony and bismuth arc the
metallic elements of Group 5 \^hich mcludes
the nonmctalhc elements nitrogen and phos-
phorus Of these elements the compounds
of arsenic and bismuth are the most impor-
tant from the standpomt of incompatibilmcs
Therefore, this discustson is restneted to
these two
Arsenic^ Inorganic arsenic is seldom used
m present day mcdicme This is primarily be-
cause Its uncertain absorption from the in-
tcstmal tract makes it unp^ssiblc to maintam
constant blood levels However, it is still
prescribed infrequently as a stimulant m its
use as a tonic or alterative m anetiuas and
skin diseases
Arsenic forms arsenous and arsemc acids
However, these are difficult to obtam except
m solution, smee the acids lose water readily
to form the oxides The arscnious oxide
(arsenous acid, arsenic trioxide) and arsenic
oxide (arseme pcnioxide) are slightly solu-
ble in water and tbcir solubility is mereased
m the presence of acid or alkali Solutions
of arsenous acid (anenic tnoxidc) generally
arc brought about by addmg HCl or potas
Slum bicarbonate to the medium, and this is
the basis for Arsenous Acid Solution and
Potassium Arscnitc Solution (Fowler's Solu-
tion) The arsenic trioxidc is feebly acidic
and, as such, reacts with alkali to form the
metallic arscnites, it can also act as a base
and thus react with acids (halogen) to fonn
the hahde
Smcc anenous acid solution and potas-
sium arsemte solution are administered singly
and not mixed with other drugs, locom-
patibiliUcs seldom arc encountered However,
if other substances are added, one must keep
m mmd the acidity of the one solution and
the basicity of the other, smee the incom-
patibih^ will be one of a pH phenomenon.
For example, m the combination of potas
Slum arsemte solution and alkaloidal salts
Strychnine sulfate 0 005
Potassium arsemte solution q s 60 0
sttychnme will be precipitated because of the
alkalmity of the solution of potassium
arsemte
Bismuth. Whereas the arsemcals used m
medicine are almost always m solution, the
bismuth compounds are highly insoluble and
are administered as powders or as suspen
siODS (exception — bismuth gljceriie) These
compounds are used largely for their me-
chanical coating of mfiamed tissue which is
accomplished through a mild astringent
action and a slow reduction of these com-
pounds to metallic bismuth in the mtestinal
tract
llie Group 5 elements illustrate quite well
die tendency for the metallic properties of
the elements withm a given group to increase
with the increase in atomic weight This ts
exemplified by the fact that the arseme oxides
arc more aci^c than basic, whereas the bis-
muth oxides are more basic than aci^c How-
ever, they are only feebly basic and, there-
fore, combine with acids to form salts which
are easily hydrolyzed Similar evidence is
presented m the fact that the electropositive
character of metals decreases with increase
lo valency, and, in consequence, the tend-
ency of the salts to hydrolyze increases Hy-
drolysis IS a common property of the halides
and other salts of the trivalcnt metals and
frequently occurs with bismuth salts m solu-
tion or suspension For example, bismuth
suboitrate m suspension readily hydrolyzes to
liberate nitric acid
2BiONO, + HOH ^ (BiOaOHNOj + HNO,
Bismuth chlondc (BiClj) decomposes com
plctely m solution according to the following
BiO, -I- HOH ?=SBiOa + 2 HQ
Suspensions and soluuons of bismuth salts
areordingly will be acidic and have the in-
compatibiliucs of acids, they cause efier-
\csccncc with carbonates and liberation of
iodine from iodides which, in turn, is con-
verted mto dark brown bismuth iodide
incompottbtliiies of inorganic Compounds 303
I O
B— I or red basic bismuth iodide Bi
\ \
I I
Prescnptions illustratmg these properties
are listed below
Bismuth submtrate
100
Calcium carbonate
80
Peppermint water, q s ad
1200
9
Bismuth subsalicylate
50
Potassium bicarbonate
100
Cenum oxalate
^0
Simple syrup, q s ad
900
The hydrolysis of the bismuth subsalicylate
hberatmg sahcyhc acid will cause a vigorous
release of carton dioxide from the calmum
carbonate These incompatibilities may be
overcome readily by subsututmg bismuth
subcarbooate for tto subnitrate or sub*
salicylate They may be overcome by allow*
mg the effervescence to go to completion and
then pourmg mto the container, but this is
time*consummg and inconvenient to both the
pharmacist and the patient It should be
understood that, when carbonates are con-
tamed m a prescription and a bismuth com-
pound IS piescnbed m combmation, the salt
of bismuth used should always be the car-
bonate, smce this does not hydrolyze to
hberate an acid
n
Bismuth submtrate 8 0
Sodium iodide 3 0
Cinnamon water, tj s ad 240 0
Bismuth compounds also are reduced quite
easily to metallic bismuth m the presence of
orgamc reducmg agents such as glyccnn (and
polyhydro:^ alcohols m general) Tins re-
duction takes place much more rapidly m
alkalme media, and, therefore, any combma-
tion of bismuth salts m which the acid liber-
ated during the h)droIysis will be removed
* through chemical combmation should be
avoided For example
9
Bismuth submtrale 100
Zinc oxide 200
Glycerm 10 0
Rose water, q^ ad 100 0
The mtnc acid that is hberated is com-
bined as zmc mtrate This prevents a lowered
pH from devclopmg and encourages further
hydrolysis which, m turn, facihtates the re-
duction to metalhc bismuth by the glycerm.
This type of mixture must be protected from
light or reducmg substances such as glycerm
must be omitted.
Because bismuth salts are so easily hy-
drolyzed with the resultmg formation of the
insoluble basic salts, almost all bismuth
(impounds used m pharmacy are insoluble
The following are examples
Bismuth hydroxide {milk of bismuth)
Bismuth subcarbonate
Bismuth subgallate (dernmtol)
Bismuth subiodide
Bismuth submtrate
Bismuth subsalicylate
Bismuth lodosubgallate
Bismuth tnbrompheoate
Groups 6 and 7
Since the incompatibihues involving mem-
bers of these groups are ionic m character,
they are considered under the respective
cation components
Group 8 Iron, Nickel and Cobalt
Of the elements of periodic Group 8, only
iron IS used to any appreciable extent m
pharmacy and medicme For this reason, pos-
sible sources of pharmaceutical incompabbil-
1 ^ which may anse from the use of other
members of the group will not be considered
Iron. Nearly all mcompatibihtics mvolv-
mg non salts are due to either (1) the m-
soIubihQr of the ferrous and the feme hy-
droxides or (2) changes m the oxidative
level of the iron salts In addiUon, incom-
patibility ansutg from the formation of in-
soluble salts such as carbonates, phosphates,
sulfides and salts formed from the dibasic
organic acids must always be considered.
The low solubility of the hjdroxides, espe-
cially feme, results m a considerable amount
of hydrolysis
Fcaj + 3HOH ^ Fe(OH), i + SHQ
304 Incompatibility and the Incompatibilities of Inorganic Compounds
A pH below 4 IS required m most cases m
order to maintain Fc+++ m solution m the
absence of special completing agents Thus,
any substance which is alkaline or \vhich
normally tends to buffer solutions above this
pH value can be considered to be incom*
pauble This would mclude such substances
as borates, carbonates, bicarbonates, acetates
and others
Precipitation of iron salts or their hydrox-
ides can be obviated m many cases by the
addition of completing agents Such sub-
stances as NHj, lactate, citrate, pyrophos-
phates, amines, sugars, polyhydroxy alcohols
(glycerin) and certam protems form co-
ordination complexes with ferrous and feme
ions which are soluble However, pharmacists
should keep in mind that the “completed”
ion may not exhibit some of the desircd
properties of the free ion (aquo ion) For
example, it is considerably less astringent be-
cause of the reduced number of Fe++ or
Fc+++ ions On the other hand, however,
the lack of this property is a desirable one
when iron u administered mtcmally Ex
omplcs of such iron complex salts arc
1 Soluble ferrous phosphate (contains
sodium Citrate to solubilize)
2 Iron and ammouum citrate
3 Feme pyrophosphate with ammonium
citrate
4 Feme citrochlonde (feme citrochlonde
tincture)
5 Saccharated ferrous carbonate
6 lion ^yeerophosphate
7 Iron nucicioate (iron with fcrronuclctc
wcvd)
8 Iron peptonale (iron with peptone)
9 Iron tartrate
10 Saccharated iron oxide
However, incompatibdity may also be the
result of such complex formation, e g ,
Fe+'*‘+ ions form complexes with phenolic
compounds such as phenol, cresols, sahcylic
acid and sabcylates, which are deeply
colored.
n
Phenol
Feme chlonde tincture
Rose water, q s ad
Bone acid
Zinc oxide
Salicylic acid
Deolooite magma, q^ ad
The supernatant liquid will turn pmk on
standing because of the iron present m the
bentonite reacung with the phenolic hy-
droxy group of the salicylic acid
The oxidizmg action of feme iron
(Fe+++) and the reducing action of fer-
rous iron (Fe++) produce many mcom-
patibihtics Hydroxy acids, mercurous salts,
phenols and other easily oxidized substances
arc readily acted on by feme ions, especially
under the influence of sunlight
Since ferrous iron is relatively easily air
oxidized, iron salts can often act as oxygen
transport systems m the atmospheric oxida-
tion of many compounds Either ferrous or
feme ions through an oxidation reduction
^clc can catalytically decompose peroxides
Agam addition of a coraplexing agent may
be helpful in reducing or even preventing
undesired oxidative changes Since the degree
of interaction is usually greater between
feme ions and complexing substances than
between ferrous ions and the same sub-
stances, the oxidative potential of the former
IS reduced considerably For example, the
electrochemical reaction
Fe++=Fc+ + + +c Eo = 0782voU
whereas
lFc(CN)8)++ = lFe(CN) 5 )+ + + + e
Eo = 0 36 volt
Lactates, ammonium ions, sugar, glycerin,
pyrophosphate, etc, exhibit approxunatcly
the same effect
REFERENCES
1 Voel, A , and Buchner, E H Chem Rev
20 169, 1937
2 Pauling, Linus General Chemistry, p 436,
Son Francisco, Freeman, 1947
3 Ibid
BIBLIOGRAPHY
But], H B Physical Biochemistry, New York,
Wiley, 1943
Hildebrand, J H Principles of Chemistry, eJ
5, New York, Macmillan, 1947 *
Sneed, M C , and Maynard, J L General In-
organic Chemistry, New York, Van Nos
trand, 1942.
Thome, P C L, and Roberts, E R Ephraim s
Inorganic Chemistry, cd 4, New York, Inter-
science, 1943
I 0
100
1000
100
100
10
1000
chapter 1 0
Incompatibilifies of Organic
Compounds
jif*( tmRABV Jf
Dale E Wurster, Ph.D.*
In this chapter a large number of the vari-
ous types of mcompatibilities encountered m
the formulation of drug products and the
compounding of prescriptions are discussed
Unfortunately, it is not practical m a stogie
chapter to discuss all the classes of chem-
ical compounds employed m pharmaceutical
preparations However, a sufficient number
of substances are treated to acquamt the stu-
dent with the kmd of information required
to recognize and solve problems pertaining
to drug stability in pharmaceutical systems
The student should ^o be aware of the fact
that the mformation presented is fully as use-
ful to explain compatibility as it is to explain
mcompatibility
The problems mentioned are primarily
chemical m nature, but some physical prob-
lems, particularly those related to solubih^,
are also discussed The emphasis on solu-
bility IS justified, as many mcompatibihties
are the result of the mitial insolubility of a
compound or the formation of a preapitate
through chemical reaction or mteraction
To avoid unnecessary repetition, calcu-
lations per tainin g to the kmetics of drug deg-
radation are omitted from this chapter, smce
this information has already been treated m
the text. Similarly, other calculations, such
as those governing whether a preapitate
would be obtamed when a given concentra-
tion of an alkaloidal salt is dispensed m an
, aqueous medium bavmg a particular pH,
have also been given previously (see C3iap-
ter4)
Lastly, mformation pertaining to the sta-
• Professor of Pharmacy, University of Wisconsin
bility of cerlam physical systems rather than
chemical compounds per se can be found m
the chapter dealmg with the dosage form
containing the particular pharmaceutical sys-
tem Thus, the correlation of the information
given m this chapter with that m the previous
chapters serves to make evident to the stu-
dent the solution of both chemical and physi-
cal mcompatibiiities
HYDROCARBONS
Saturated Hydrocarbons
This class of chemical compounds is rep-
resented m pharmaceutical dispensing by
hquid petrolatum, petrolatum and paraffin.
Although the actual number of substances
of this class which are used is not great,
the above-mentioned agents are employed
extensively
Solubihty. The saturated hydrocarbons are
nonpolar compounds and, therefore, are m-
solubJe m water and other polar solvents
However, these substances are miscible with
other nonpolar solvents such as ether, ben-
zene, petroleum ether, chloroform, carbon
disulfide and fixed oils as a result of mduced
dipole-mduced dipole mteractions
Incompatibdity. Inasmuch as the alkanes
are extremely unreactive substances, they give
nse to no incompatibihues m prescriptions
due to chemical reactions However, they do
cause many incompatibilities of a solubility
nature The members of the alkane senes do
not react with acids, alkalies or oxidizing or
reducing agents In order to bring about a
change m their structure, either extremely
305
306 Incompohbiliiies of Orsanic Compounds
hi^ temperatures, strongly electrophilic
(electron-seeking) reagents or both usually
arc required.
Incompatibilities in prcscnptions involving
the saturated h) drocartons arise mainly from
attempts to mu these nonpolar compounds
with polar compounds The same prmciples
apply both in hquid preparations containmg
liquid petrolatum and in ointments contain-
mg petrolatum In either ease, if water is in-
cluded, whether alone or with dissolved sub
stances, compatibility can be attamed only
through emulsihcation
ALCOHOLS
The alcohols may be considered as hy-
droxy dcnvativcs of hjdrocarbons The sub-
stitution of a hydroxyl group for a hydrogen
of a hydrocarbon causes profound changes
m both the chemical and the physical prop-
erties with the change m solubility charac-
teristics being particularly evident loasmudi
as alcohols may contam one or more hy>
deoxyl groups, they are classiSed as mono-
hydroxy and polyhydroxy compounds
Monohydroxy Alcohols
Solubility The alcohols are miscible with
water by virtue of tbcir ability to ossoaate
with water through hydrogen bonding. From
a practical pharmaceutical standpomt, propyl
and isopropyl alcohol represent the upper
limits 01 solubility of alcohols m water, al-
though normal butyl alcohol is soluble to the
extent of 7 9 Cm per 100 ml and amyl alco-
hol to the extent of 2 7 Gm per 100 ml of
water As the alkyl cham of the monohydroxy
alcohols is mcrcascd beyond certain limits
(4 to 5 caibon atoms) , these alcohols become
less polar and lose their abihty to compete
with the more polar water molecules for a
place m the association complex They then
arc replaced by water molecules and become
immiscible
Alcohols ore miscible with or solubil-
ize other substances containing hydroxyl
(—OH), amino (— NH 2 ) orimino (— NH)
groups having hydrogen as the positive end
of a dipole with whi^ the alcohol can asso-
ciate Thus, the alcohols arc capable of solu-
bilizmg substances such as alkaloids, car-
Table65 Solubilities of Some
Monohydric Alcohols
Solubility in Gm
PER 100 ml op
Alcohol Water Alcohol Ether, etc
Methyl alcohol
CO
CO
CO eth.
Ethyl alcohol
CO
CO eth , ch] ,
me al
Isopropyl alcohol
CO
eo
09 eth
n Butyl alcohol
7920
00
CO eth
Isobutyl alcohol
12520
CO
CO eth.
n Amyl alcohol
272*
00
so eth.
n Hexyl alcohol
0.59*0
eo
CO eth.
eth. s ether
chi ^ chlorofonn
me. aL = methyl alcohol
00 = soluble m all proportions
boxylic acids, phenols, resms, balsams,
barbituric acid dcnvativcs, etc and may be
added to aqueous preparations contaming
these substances to prevent preopitatjon
IncompaubiLty, Alcohol precipitates many
substances such as tragacaoth, acacia, agar,
other plant gums that are carbohydrate m
nature, atbuoun, gclatm and other proteins
from aqueous solution These substances are
precipitated because the alcohol acts as a
dchydraUng agent The alcohol possesses
such an a&uty for the water that the two
readily associate and destroy the association
existing between the gums and the water
Many morganic salts are precipitated from
aqueous solutions by the addition of alcohol
POLYHVDROXY ALCOHOLS
Ihe polybydroxy alcohols demonstrate the
relationship that exists between the number
of hydroxyl groups and the molecular weight
of the compound. When the ratio of the
hydroxyl groups to the carbon atom content
is mcreased, the result is an increase m di-
electric constant, polanty and soIubiUty in
water The glycols, glycerin and carlwhy-
drates arc examples of compounds of this
class which are used m pharmaceutical dis-
pensing Incompatibilities of a solubility na-
ture are encountered when these substances
are mixed with nonpolar substances that are
incapable of association through hydrogen
bond formation
Alcohols 307
Carboliydrates. Tbe carbohydrates mdude
substances such as the sugars, the stardies,
tbe pectins, the celluloses and many other
substances closely related to them
Sugars Tbe sugars which are used m
pharmaceutical dispensmg are classihed ac>
cordmg to their behavior toward hydrolytic
agents (e g , monosaccharides, disacchandes,
etc ) These classes are also subdivided mto
groups, depending on whether they are re-
duemg sugars (e g , glucose, fructose, mal-
tose, lactose) or nonreducing sugars (eg,
sucrose)
Solubility The monosaccharides and the
disacchandes are soluble m water in spite of
their relatively large molecular wei^t, since
they have a suffiaent number of hydroi^l
groups in the molecule to promote solubihqr
Water dissolves these substances by associa-
tion through H bond formation. They are
shghtly soluble m alcohol for tbe same rea-
son, although to a much more limited extent
Incompatibility Alcohol causes the pre-
cipitation of sugars from concentrated solu-
tions This may be explamed on the fol-
lowmg basis the alcohol competes more
efficiently for water, associates with it and
forces the sugar out of soluuon
The sugars are oxidized easily and. when
triturated m the dry form with strong oxi-
dizing agents such as permanganates, per-
oxides, picnc acid, etc , they form explosive
mixtures The disacchandes arc hydrolyzed
by acids In alhalme solution, the reducing
sugars turn dark because of the formation of
decomposition products
Gums Tbe plant gums acacia, agar, chon-
drus, sodium algmate and tragacantb are car-
bohydrate m nature and find use m pharma-
ceutical dispensmg as dispersion slabihzeis
m polyphase systems such as emulsions and
suspemous
Solubility These hydrophihc substances
become hydrated to form gels due to the
presence of the hydroxyl groups in the mole-
cule Their water solubihty is thus attributed
to their abihty to associate through hydrogen
bonding
Most of the plant gums require a consider-
able amount of time to hydrate completely
to form homogeneous preparations &tem-
poroneous preparations con be made by tritu-
rating the gum with a small amount of water-
soluble hydroxyr compound such as alcohol
or glycerin They are insoluble m the alco-
hols, and, when tnturated together, each
small particle of the gum becomes surrounded
with ^cohol On the subsequent addition of
water, the alcohol and the water associate
through hydrogen bondmg, and the water is
thus drawn through the mass so that each
small particle of the gum is surrounded by
water Therefore, hydration of the gum takes
place more readily and a homogeneous mucil-
age IS obtained more rapidly than when w ater
alone is used This techmc may be employed
for acacia, tragacanth, mcthylccUulose, etc
Incompatibility The gums are dehyihated
and precipitated by alcohol with a resulting
decrease m viscosity They are also precipi-
tated by heavy metals
Agar. The chemical consututioa of agar
has been shown to be a magnesium or a cal-
aum salt (or a mixture of these two) of a
sulfunc acid ester of a linear polygalactose **
Proposed Stniciure of Agar*
Agar IS dehydrated and precipitated from
aqueous preparations by the addition of al-
cohol Tonnm also has a dehydrating action
oQ agar similar to that of alcohol, but is elTec-
tive in a much lower concentration Whereas
the alcohol must be m excess of 50 per cent
by weight, a 1 per cent concentration of
tannic acid causes precipitation There is also
a difierence between the two m tbe mecha-
nism of dehydration It is believed that the
tannin is adsorbed on the surface of the col-
loidal particles m such a manner m this com-
plex that tbe sugar portion of the tannm
molecule is orientated toward the surface of
the agar and the aromatic groups toward tbe
dispersion medium, or water Tbe external
nature of the agar is changed m a manner so
as to curb or suppress hydration “ A small
amount of alcohol will restore the hydro-
303 Incompatibilities of Organic Compounds
philtc property of the agar by removing the
adsorbed taamn
Electrolytes m adequate concentration
(0 1 N and above) compete with the colloid
for the water which is present, thus causing
dehydration and a decreased viscosity of sols
Due to the presence of the sulfunc acid ester
m the molecule, agar ionizes to yield a nega-
tively charged hydrophilic colloid which may
form a coacervate with an oppositely charged
colloid with a resulting decrease in viscosity “
Chondrus (Irish Moss) This is chemi-
cally similar to agar and resembles agar m
Its physical and chemical mcompatibihtics It
forms a soft gel at 3 per cent and a firm one
at 5 per cent concentrabon
Sodium Alginate This is the sodium salt
of algmtc acid Although the structure of al-
gimc acid is mcompletely known, it is be-
lieved to be a polyuronic acid Algmic acid
is insoluble m cold water and only shghtly
soluble in hot water However, the magne-
sium, ammonium, potassium and sodium salts
possess hydrophilic properties Sodium al-
ginate t$ soluble 1 20 m water
Proposod Slnicture ol Algmic Acid*
Addition of soluble calcium salts to aque-
ous solutions of sodium alginate yields the
insoluble calcium aigmate which pceapiutes
as a gel A similar gel formauon is obtamed
by all other metallic ions, with the exception
of alkali, magnesium and ammomum ions
Sodium aigmate solubons are compatible
with sugars, soaps, glycols, glyccnn, starch,
protems and a number of dispersion st^i-
lizcrs At a pH of less than 4, precipitation
occurs due to the formabon of the insoluble
algmic acid. Mineral and orgamc acids m
small quantibcs arc a source of this mcom-
paubility Above a pH of 10, sodium algi-
nate IS unstable, and there is a decrease m
viscosity Once agam, alcohol m sufficient
quanbty (above 30 per cent w/w) causes
prccipitabon from aqueous solution
Acacia The acacia molecule contains
d galactopyranosc, d glycuromc acid,/-rbam-
nopyranose and /-arabofuraoosc, and exists
m the form of the calaum, the magnesium
and the potassium salts It owes its acid-
ity to the presence of d-glycuronic acid
Acacia is sufficiently acidic to cause effer-
vescence with carbonates and bicarbonatcs
It IS precipitated by heavy metal ions Com-
mon precipitabon mcompabbdities occur
with feme chloride, lead subacctatc, tannins
and sodium borate The precipitabon occur-
ring due to the alkalmity of the sodium borate
may be retarded by the addibon of glycerin
This yields a weak acid solution by forming
a sodium glyceroboratc and glyccrobonc
acid buffer system- Alcohol (above 35%)
precipitates acacia by actmg as a dehydrabng
agent
Acacia is stated to contam an oxidizing
enzyme'^ which is capable of causing incom-
paubihucs with the easily oxidized phenolic
compounds such as rcsorcmol, phenol, thy-
mol, tannin, etc * Other substances contain-
ing phenolic hydroxyl groups m their mole-
cule (e g , morphine) are affected similarly **
Tracacanth According to Norman,®*
tragacanth is composed of a water-soluble
fracbon (called tragacantinn) and bassorm,
which swells m water The water-soluble frac-
bon consists of uronic acid and arabmose
Rowson’® showed that the bassorm contains
methoxyl groups and is similar to pecUn m
composibon
Tragacanth is precipitated by alcohol
(above 35% ) and decomposed by alkalies
Cellulose Derivatives Mcthyiccllulose
(Methocel) is used as a dispersion stabilizer
la polypb'ase systems because oi its ability to
increase viscosity Wide ranges m viscosi^
arc possible through the use of the various
viscosity types f
* Tlie mechanum of these oudaUoo reactions is
pn^bl/ similar to that brought about by tyrosio
ase Tyrosinase u responsible for the black colora
tioQ observed in potatoes bananas etc., when they
are exposed to air The enzyme tyrosinase u capable
of introducing a hydroxyl group in ortho position
to the —OH group already present in phenols
o>DihydroxyIic phenols are readily autoxidizable in
alkaline solution or in neutral solution
t A 2 per cent solution of tncthylcellulose of the
100 cps viscosity type has a viscosity of 100 centi
poises at 20* C Metbylcellulose is available m the
follotsing viscosity ty^ IS cps, 25 cps, 100 cps,
400 cps 1,500 cps and 4 000 cps. Tuo per cent
solutions of these viscosity typM yield solutions
varying from low to very high viscosiues
Alcohols
309
Solubility METHYLCELLULOSE IS WatCT-
soluble and forms viscous, transparent, neu-
tral solutions The water-soIubility of methyl-
cellulose IS m marked contrast with Ae
parent compound, cellulose The difference
m the water-solubility of these two substances
may be explamed on the following basis
Cellulose is insoluble m water because of
the mtermolecular association exisUng be-
tween the cellulose molecules This associa-
tion between the cellulose molecules ties up
the hydroxyl groups so that they are unavail-
able for association with water When cellu-
lose IS methylated,* association between the
cellulose molecules is hmdered to such a de-
gree that free hydroxyl groups are exposed
and become available for association with
■water
CHj O-CH, H 0 CH, CH, 0 CM,
BO CH, kt^OH
Representation of Random Outribution of Metboxyl
Groups in a DunetbylceLlulose
Incompatibility Methylcellulose is precipi-
tated from aqueous solutions by heat Ther-
mal agitation causes the water molecules to
move about more freely, and the weak asso-
ciation bonds are ruptured, thereby causmg
a decrease m the water-solubility of the
methylcellulose This effect of heat m de-
creasmg the water solubility also occurs lo
other alcohols
tions However, dilute alkahes do cause a
slight mcrease m viscosity
Tanmc acid mteracts with methylcellulose
and causes it to be precipitated from aqueous
solution Similar complexes which result m
the precipitation of the methylcellulose are
formed with other phenols such as resorcmol
Unlike the plant gums, methylcellulose in
aqueous solution is not precipitated by rela-
tively high concentrations of alcohol
Inasmuch as methylcellulose is nomonic,
It IS compatible with the commonly employed
dispersion stabilizing agents, such as plant
gums, soaps, bentomte, sodium lauryl si^ate
and benzalkomum chlonde
ETHYLCELLULOSE (Ethoccl) IS the ethyl
ether of cellulose It does not hydrate m water
but IS solubilized m orgamc solvent systems
such as one composed of equal parts of
chloroform and isopropyl alcohol It is used
to form water-msoluble films to control both
drug stability and drug release m granules
and tablets The water resistance of the films
can be decreased by the mcluston of water-
soluble substances such as methylcellulose,
polyethylene glycols and polyvmyl alcohol
CARBOXYMETHYLCELLULOSB (CelluloSe
Gum, CMC) can be represented as the prod-
uct of the type of reaction such as that be-
tween alkah cellulose and sodium mono-
chloroacetate in which a subsUtution of ap-
proximately 0 75 carbo^methyl group per
onhydroglucose unit is obtamed m the
polymer
Aqueous methylcellulose solutions arc
stable over wide pH ranges (pH 2 lo 12)
and, therefore, are not affected appreciably
fay alkalme and acidic substances m presenp-
* Within certain limits, an increase in the nomber
of melhox)! groups per anhjdroglucose unit in*
oea&cs the water solubility Those cellulose denva
tiles contaiiung an average of 1 3 methoxyl groups
per anbydroglucose unit are water insoluble When
the number of methoxyl groups per anhydroglocosc
unit vanes between 1 3 to 2 6. the products are
soluble in cold water, above 2 6 methoz)! groups
per anhjdroglucose unit, the compounds breome
less water soluble but they are more soluble in
alcohoL
^ + NaCl
Like methylcellulose, carboxymethylcellu-
lose IS available in. vanous viscosity ^ades
(Hercules CMC-70-H, CMC-70-M and
CMC-70-L) The sodium carboxymethylccl-
lulose is eas Jy hydrated with water as a result
of both lon-dipoIe and dipoIe-dipoIe mterac-
tions The pH of 1 per cent solutions of the
viscosity-inducmg agent is m the 6 5 to 8 0
range Carboi^methylcellulosc solutions are
very stable to acid and do not precipitate
until the pH is below 1 1 This pH would not
be encounteied normally m pharmaceutical
preparations SoluUons of this agent also tol*
310 Incompahbilihes of Organic Compounds
Table 66 Solubilities of Some Phenols
Phenol
SOLUBIUTY IN GM PER 100 ML.
Water
Alcohol
Ether, etc
Betanaphlhol
0074“
12525
76S eth , s chi , oils, alk., gly.
Catechol
45 I*®
V 5
s eth . bz., chi , alk.
Chlorolbymoi
almost!
200
50chl.50bz.66.5etb,s alk
Crcsol
2 0"®
eo
eo eth , s chi , ord org solv
Hcxylrcsorcinol
005
v.s
V s eth.
Phenol
67>«
CO
V s eth , s chi , gly , alk
Pyrogallol
62 5»
10025
83 3 eth , si s bz., chi
Resorcinol
229"
243“
V s eth , s gly , bz.
Thymol
0 0352®
35720
360 eth , s cU . si s gly
alk. = aikali eth. =c ether
bz. 55 benzene gjy = glycerin
chi ssMorolona eo = soluble mail proportions
crate high cocccntratiOBS of alcohol (up to
50%) without precipitating
Hov^’ever, some problems are encountered
when solutions of Cellulose Gum arc mixed
with solutions containing water soluble salts
such as alumiQuin sulfate, silver nitrate, fer*
nc chlonde and lead acetate Several vis>
cosity inducmg agents such as methylceilu*
lose, pectin, sodium alginate and polyvmyl
alcohol are compatible with aqueous solutions
of carboxymcihylcellulosc, but delayed in*
compatibilities were observed with gelatin,
acacia, t^ondnis and tragacanth
PHENOLS
Chemically, the phenols fall into (be same
class as the ^cohols, but the presence of the
aromatic nng lo the phenols greatly modifies
their chemical and solubility properties
Solubility. Although the phenols are acidic,
they arc too \\ cakly acidic to dissolve la water
through an acid base reaction, but they arc
solubilized m water through dipoIe-dipole
tcraction m the same manner os the alcohols
The introduction of more —OH groups into
the aromatic nng mcrcascs the water solu-
bili^, whereas nonpolar substituents decrease
the watcf-solubility
Cause of Acidity. The cause of acidity and
the marked contrast m chemical properties
between the phenols and the aliphatic olco*
hols arc due to the presence of the acidic
(electrophilic, electron acceptor) phenyl
group The unsaturated, elcctron-dcficieot
phenyl group tends to withdraw the surplus
electrons on the oxygen In supplying a share
of Its unshared electron pair to the phenyl
group, the oxygen becomes electron deficient
The electron pair of the oxygen-hydrogen
bond, therefore, is held more closely to the
oxygen The oxygen hydrogen tood is thus
weakened and the proton held more loosely
This accounts for the acidic properties of
phenols in which there is a tendency to ionize
m aqueous solution by donating a proton to
the more basic compound, water
:o:-
+ h:osh -♦ + h;o;h
j u ~
Fbcnols are only weakly acidic and do not
ionize sufficiently to be highly soluble m
water unless the aromatic rmg has other
acidic substituents which increase their aad
properties, or other solubilizing groups (OH,
NHs) which mcreasc their ability to associ-
ate However, the phenols arc sufficiently
acidic to be readily soluble in dilute aqueous
alkali hydroxides by virtue of the fact that
they are capable of forming water-soluble
ionized salts
OH o"
Phenols 311
Unless they have other acidic substituents,
they are weaker than carbonic acid and the
water-insoluble phenols are precipitated from
aqueous alkali solutions by carbon dioiude
Inasmuch as they are such weak acids, they
do not decompose carbonates or bicarbonates
The mtroduction of other acidic (electro-
philic) groups mto the aromatic nng m-
creases 5ie unequal sharmg of the electron
pair of the oxygen hydrogen bond and makes
the compound a stronger acid This elTect in
increasing the acidity is illustrated clearly by
trmitrophenol (picnc acid), which is a much
stronger acid than phenol itself The dissoci-
ation constants hsted m Table 67 show the
difference in acid strength between phenol,
carbonic acid and trmitrophenol
Chemistry. The result of the electron shifts
IS an increased electron density on the ortho
carbon atom which, m turn, mcreases the
electron density on the para and the other
ortho carbon atoms The ortho and the para
positions thus react readily with electrophilic
(electron seekmg) reagents, e g , phenol is
easily nitrated m the ortho and the para
positions
The electronic theory shows us that bases
are capable of donating electrons and that
acids are electron acceptors When the phe-
nomenon of oxidation reduction reactions is
taken mto consideration, it is observed ibat
reducing agents donate electrons or a share
in their electrons to the oxidizing agent From
the standpomt of the fundamental electronic
concepts mvolved, an analogy can be drawn
for bases and reducing agents and acids and
oxidizing agents Both bases and reducing
agents, therefore, arc electron donors, whereas
acids and oxidizing agents are electron ac-
ceptors ^ "*
Consequently, phenols are reducing agents
because the oxygen possesses unshared elec-
trons and functions as an electron donor It
has long been known that oxidizing agents
such as peroxides, permanganates, air, etc.,
arc capable of oxidizing phenols to colored
oxidatue products, and these same reactions
may gi\e nsc to incompatibilities in prescrip-
tions Phenols give characteristic color reac-
tions With feme chloride In this reaction, the
iron functions as the oxidizing agent and is
reduced to the ferrous state Other important
Table 67 Dissociation Constants
K.
Temp
CC)
Phenol
1 3 X 10-u»
25
Tnnitrophenol
Catbonic acid (first
I 6 X 10-1
IS
hydrogen)
3 5 X 10-^
IS
Ethyl alcohol
7 3 X 10-20
drugs classified under other chemical groups
such as dicthylstilbestrol, epmephrme, mor-
phme, rutm, etc , which have phenolic groups
in the molecule undergo similar reactions
Phenol is soluble m water to the extent
of 6 7 Gm. per 100 ml and is readily soluble
in ali»hol, ^ycenn and aqueous solutions of
alkali hydroxides
Phenol interacts with protems to form
water insoluble complexes This is the cause
of the corrosive action of phenol on the
skin Phenol should be removed from the
skm with alcohol rather than water, due to
Its greater solubility m the former solvent
Phenol m-ojJ solution does not cause the ex-
tensive tissue necrosis such as aqueous so-
lutions cause, but its effectiveness agamst
micro-organisms is also decreased Phenol is
precipitated from aqueous solution by solu-
ble heavy metal salts It forms liquid or soft
masses with many organic compounds such
as belanaphthol, camphor, chloral hydrate,
menthol, lead acetate, pyrogallol, resorcinol,
tbyrmol, other organic compounds possessing
low meJliDg points and functional groups wjih
which It can interact
The oxidation of phenol to colored de-
composition products by peroxides, perman-
ganates and other oxidmng agents takes place
in the same manner as stated m the general
discussion of phenols Alkali hydroxides ac-
celerate its oxidation and, thus, autoxidation
by air m aqueous alkali solution occurs at a
rapid rate
CRESOLlCeHifCHj)©!!] Cresol IS a mix-
ture of the 3 isomenc crcsols and is simiTar to
312 Incompatibilities of Organic Compounds
phenol m its chcoucal properties The effect
of nonpolar substituents on the aromatic nng
IS sho\\‘n clearly in the case of the cresols,
thus ^^e find that they are only about one
third as soluble in water as phenol (approt
2 Gm per 100 mL) Crcsol is freely soluble
m alcohol, glycerin, ether, fixed oils, solu-
tions of alkali hydroxides and soap solutions
Creosote consists chiefly of cresol, oxy-
crcsol, methyl crcsol and other phenols It is
only slightly soluble in water but is readily
soluble m alcohol and fixed oils It has reduc-
mg properties and is mcompatible with oxi-
dizing agents Proteins and gums are precipi-
tated by cresol Color reactions are obtamed
with feme salts
\s not very vjattt-scAuWo
(1 1,000} and it, too, illustrates the effect of
decreasmg the water solubility by mcreasiog
the molecular weight without an accompany-
ing increase m the number of bydrophUe
groups Betaoaphtbol is very soluble in alco-
hol, glycerin, uxed oils and dilute solutions
of alkidi hydroxides In the presence of light
and air, betaoaphthol is oxidized and turns
pmk to brown with the formation of colored
oxidation products Other oxidizing agents
such as peroxides, permanganates, chlorates,
etc , have a similar effect In alkali hydroxide
solutions, the oxidation reactions take place
more readily Soft masses or liquids are ob-
tamed when betaoaphthol is tnturated with
phenol, menthol, camphor, etc
Resorcinol is much more soluble m water
than IS phenol and illustrates the abihty of
an mcrcascd number of hydroxyl groups to
promote greater water-solubility It is also
soluble m alcohol and glyccnn In aqueous
solution, resoremol is oxidized and the solu-
tion assumes pmk to red and brown colors
because of the formation of colored oxidative
products Resoremol is a reduemg agent,
especially in alkalmc solution, and it is capa-
ble of reduemg silver, mercury and copper
salts Even m omtmcnts, for example, it is
capable of reduemg ammomated mercury to
free mercury The free metal thus hberated
causes the omtment to assume a blue to gray
color Blue to violet colors are obtamed with
feme chloride On tnturation with substances
such as camphor, menthol, phenol, beta-
naphlhol, etc , soft masses or liquids result
llcxylrcsorcmol (Caprokol) is almost m-
soluble m water (0 05 Gra per lOO ml ) but
IS very soluble in alcohol and ether It is also
soluble m glycerin and fixed oils The mtro-
duction of the alky group produces decreased
water-solubihty as compared with resoremol
Hexylrcsorcinol is similar to resoremol m its
chemical mcompatibilities
Thymol ( 3-hydroxy- 1 -methyI-4-isopro-
pyl benzene) is almost insoluble m water
(0085 Cm per 200 ml) The decreased
watcr-solubiLty as compared with phenol is
due to the nonpolar substituents on the aro-
matic rmg Thymol is soluble in alcohol and
ddute solutions of alkali hydroxides It forms
liquids or soft masses with camphor, men-
thol, chloral hydrate, phenol, etc
Chlorothymol is similar to thymol m its
properties
CH,
^CH
CH, ''CH,
Trinitrophesol (picnc acid, 2,4,6-ln-
nitrophcnol) is a strong acid (p 310) Ex-
plosions may result when picric acid m the
dry form is tnturated with substances which
are oxidized easily, or when the acid is sub-
jected to rapid hcatmg or percussion Picric
aad precipitates protems (gelatin, albumm,
etc) and most alkaloids Because of this
Aldehydes 313
OH
NO}
latter property, it is used ss an alkaloidal
reagent
ALDEHYDES
Solubility. The lower members of the alde-
hyde senes are soluble m water but those of
C 5 and above are only shghtly soluble or m
soluble Thus, these compounds have approx-
imately the same limits of water soIubihQr as
the monohydroxy alcohols
Chemistry^ The tcacUons of the aldehydes
are a function of the carbonyl group As illus-
trated m the following equation, there is a
H H H
I /~v ^
R — C = 0 or RaCSo 0-^ RoCoO*
r
tendency for the electrons of the carbon
oxygen bond to break away from the carbon
and to collect on the oxygen
This causes the carbon to become charged
positively due to the electron deficient^,
whereas the oxygen atom has gamed a share
of electrons and becomes charged negauvely
As a result of the electron deficiency, the car-
bon becomes one of the reactive centers 10
the molecule and reacts with any reagent that
has available electrons for attachment In all
the addition reactions of the aldehydes, it is
observed that the more positive part of the
reagent joins to the ci^gen and the negative
part joins to the carbon.
1 Addition of sodium bisulfite
H H
H-6-O + KflHSO.— » fl— C-OH AWehy<Je4)BuIfite
* I Compound
SO,Na
Table 68 Comparison of Water-
SoLUBiLiry OF Some Aldehydes
AND Alcohols
Compound
Solubility in
Cm per IOO
ML ofHiO
Aldehyde
Aceuldehyde
CO
Pfopiooaldehyde
en
Butyraldehyde
37
n Valeraldehyde
si s
n Caproaldehyde
t.
n Heptaldehyde
si s
Alcohol
alcohol
BO
Propyl alcohol
oO
Butyl alcohol
7920
Amyl alcohol
2.7»
Hexyl alcohol
0.59"
Heptyl alcohol
009”
The carbonyl group also has an important
effect on the hydrogen attached to the o-car-
boo atom Smee the carbon atom of the
carbonyl group is deficient m electrons, it
tends to withdmw the electrons bonding the
hydrogen on the o-carbon atom. In this case,
a tautomeric shift rather than resonance oc-
curs because the hydrogen shifts from the
carbon atom to the oxygen However, this
does account for the reactivity of the a-hydro-
gen Thus, m the preparation of chloral, the
hydrogen is substituted easily by chlorme
/
CH,~C=0 +3CI, »CC1,— C=0 -I-3HCI
2 Addition of HCN
R-e>0-f HCN-
Aldehyde
Cyanohydrin
3 A ddition of hy droxy lamme
R-i—o
R-C— 6H
NHOH
H /*
HC— C=0^
H
=H2C=C-0H-i-C^-
HC-C-^
Cl fg I
♦ HCI+H-C-C=0
314 incompotibilities of Organic Compounds
♦HC=C“0H + a,-
f-*Hatc»-c-c=o
iCl-C=C-OH+CU-
Cl-C-C-O H
*cci,-c=otHa
Trtchlor
aceialtlebyde
Aldch}dcs arc capable of addition reac-
tions with water via the same mcebamsm as
the other addition reactions In aqueous solu-
tion, this equilibrium exists but the dih>droxy
compound ts usually too unstable to be iso-
lated However, the halogen-substituted alde-
hydes such as trichloro3cctaldch)de (chloral)
form stable addition products with water
1 1
CCJ,— C=0-h HOH— ♦CCI,— C-OH
OH
Chloral Chloral Hydrate
For)'mcnz3iion ta&es place with the afde-
hjdcs due to the polanzaiion present m the
carbonyl compounds, as previously explained
SOLUTION OK
Aldol
1CH,-C=0>, ^[^°"°> lieCKTOC SESm
Paraldehyde Although it is an acetal
rather than an aldehyde, paraldehyde is in-
cluded at this point, smee its mcompati-
bilitics ore a result of the regeneration of
acetaldehyde Paraldehyde is a colorless
transparent liquid possessmg a pungent odor
and a disagreeable taste It is somewhat solu-
ble m water ( 1 ml m 8 ml ) and is soluble
in all proportions in alcohol Paraldehyde is
inert to oxidizing agents and does not fonn
addition products because the carbonyl group
IS no longer present In dilute acid, acetalde-
hyde IS regenerated Thus, acid syrups and
elixirs used as vehicles may promote the de-
polymerization of paraldehyde The liberated
acetaldehyde may then give nse to many
iDCompatibilitics, such as the formation of
the usual addiDon products
Because of its bad taste and odor, paralde-
hyde has not much populanty m present-day
medicine, but it is actually one of the best
and the least toxic of hypnotics Its use in
the fonn of an emulsion has previously been
recommended "
Paraldehyde detenorates through oxida-
tion on standing, becomes more acid*' and
3CH,-C-HC
Ae«lal4t)iy4«
CH,
0*^
Incompatibility. In the presence of alkali,
aldehydes undergo aldol condensation. The
extent to which the reaction progresses is de-
pendent on the concentration of the alkali
With strong alkali, aldehydes polymerize to
form resins
liberates free iodine from iodides The acid
which IS formed as a result of this oxidation
IS probably peracetic acid
Formaldehyde When solutions of form-
aldehyde arc evaporated to dryness, a mix-
ture of polymers known as the polyoxy-
Aldehydes 2\S
methylenes is fonned. Aqueous formaldehyde
solutions are quite stable, which mdicates
that the formaldehyde exists m equilibrium
with the hydrated compound formed by an
addition reaction with water On evaporation,
water is elimmated from successive mole-
cules of the formaldehyde hydrate to give
nse to a mixture of polymers referred to as
paraformaldehyde Aqueous solutions of
formaldehyde which are subjected to cold
temperatures are subject to the formation of
par^ormaldehyde which settles out as a
white preapitate Sulfunc aad also induces
the reaction
electromenc effect present m the carbonyl
group, creates a center of low electron den-
sity on the carbonyl carbon atom so that ad-
dition reactions with nuclcophihc reagents
(electron donor) readily take place
Chloral Hydrate
In a sunilar manner, chloral forms chloral
alcobolate by addition Chloral alcoholate
H H j_
H-c=:o + HOH=^H-C-OHFormaldebyde Hydrate CCI,-C-0 + H0-CHj-CH, ►
OH
Y / 'i \ 't
H-C-OH +jH-C-OH| +HO-C-H ►
OH \ OH / OH
V
H-c-(o-en.v<>-f
OH OH
(Polyozymetbyleoe)
Paraformaldehyde is slowly soluble m cold
water, it is readily soluble m hot water with
the formation of fonnaldehy de It is insoluble
m ether and alcohol Inasmuch as heat causes
the regeneration of formaldehyde from para-
formaldehyde (Paraform), the latter com-
pound IS used for fumigation purposes
Strong oxidizing agents oxidi^ formalde-
hyde to formic acid, and alkalies produce the
formaldehyde resin
Qiloral Hydrate This is very soluble
m both water and alcohol The stability of
this hydrated form of chloral may be ex-
Cd.-C-OH
• I
OH
plamed on the basis of the mductive effect
of the halogen substitution on the a-carbon
atom Just as m the case of the chlorinated
acetic acids, the electrophilic chlorine groups
on the o-caibon atom tend to withdraw el^-
troos This mducUve effect, together with the
CC«,-CH
OH
Chloral Alcoholate
may be formed in hydroalcobolic solutions
cootainmg high concentrations of extremely
water-soluble salts such as sodium and potas-
sium bromides, acetate, citrates, sulfates,
sugars, etc In this case, the chloral alcoholate
separates as an oily layer which also contains
cbJoral and alcohol In solutions containing
less than 10 per cent alcohol, chloral alco-
bolate does not form, regardless of the salt
or the chloral hydrate concentrations ** In
solutions contoxnmg between 10 and 50 per
cent of alcohol and a high salt concentration,
the chloral alcobolate is formed readily and
separates as an inumscible layer due to the
saliujg-but effect of the high concentration
of the water soluble salt In solutions con-
taining above 50 per cent alcohol, the chloral
alcoholate does not separate because the salt
concentration necessary cannot be as great
m this high alcoholic solution Furthennore,
chloral alcoholate is lery soluble m both
water and alcohol, and, if formed, ivould dis-
solve readily m the excess of alcohol No diffi-
culty IS encountered m solutions which do not
contam the highly water soluble salts regard-
less of the alcohol concentration because
chloral hydrate is very soluble m both water
and alcohol and the saltmg-out effect is ab-
sent Actually, chloral alcobolate is less toxic
and less hypnotic than chloral hydrate,’ but
when it separates out as a layer at the top
316 Incompatibilihes of Organic Compouadt
Table 69 Comparison of Water-
Solubility OF Some Ketones
AND Alcohols
COMFOUSD
Solubiltiyin
Gm per IOO
ML OPHaO
Keione
Acetone
09
Ethyl methyl
35 3«
Diethyl
47»
n-Propyl ethyl
v si s.
Di n propyl
L
Alcohol
Ethyl
M
Propyl
eo
Butyl
79-0
Amyl
27 a
Hexyl
ossro
Heptyl
0 09‘»
of the bottle, the danger lies in taking too
Urge a quantity m a single dose
In aqueous solutions, chloral b)drate
slosvly decomposes Li^t accelerates this
decompositioo. Chloral hydrate in aqueous
solution is incompatible with alkaline sub-
stances and undergoes b)drolysis to form
chloroform and the salt of formic aad. Due
to this reaction, sodium phenobarbitol, so-
dium dipbenylh)dantoiaate and other salts
which yield alkalme solutions may cause the
hydrolysis of chloral hjdratc and the subse-
quent precipitation of the free phenobarbi-
t^ etc
H
CC1-— C —OH +N0OH — »CHCI. +
* I »
OH
Chlon] Chlor^
llydrato form
r /O"*! /
[h- ^-o| h]|-»hc-oh»»h^o
1 foH 1 1
*• ‘ ** formato
On oxidation, chloral hjdrate yields
trichloroacetic acid (CCIr-COOH), on re-
duction, It fields tiichloroethanoi (CCHy-
CH,OH)
Chloral hydrate forms sc(t masses or
liquids when tniuratcd with acctopheoetidm,
camphor, cocoa butter, menthol, phenol, thy-
mol, salol and many other substances
KETONES
Solubility. Like the aldehydes, the ketones
haw approximately the same bmits of solu-
bility m water as the monohydroxy alcohols
Those above C5 are only slightly soluble or
are insoluble m water
Chemistry. Because the ketones contain
a carbonyl group, many of them undergo the
same addition reactions as the aldehydes,
however, the subsutuuon of an alkyl group
for the hydrogen atom markedly decreases
the additive reactivity of the carbonyl group
If one compares the activity of acet^debyde
and acetone in the formation of the bisulhte
addition compound, it is observed that ace-
tone reacts much less rapidly and to a lesser
extent This may be explamcd on the basis
that the methyl group in acetone which has
been substituted for the hydrogen atom m
acetaldehyde is an electron repellent group
This group then tends to decrease the electron
deficiency of the carbonyl carbon atom, de-
creases the poIanzatjoQ of the molecule, and,
consequently, the carbonyl carbon atom is
less reactive with the electron donor reagents
8 -
c,
CH,-C — CH,
* a* *
Because of their decreased polanzation,
the ketones arc less susceptible to polymcn-
zation than the aldchy dcs
In pharmaceutical dispcnsmg, ketones give
nsc to few mcompatibilitics because they
seldom appear as such m prescriptions, with
the exception of camphor and, to a vciy
limited extent, acetone Since the polarizing
effect of the carbonyl group docs not lead to
any important chcmic^ mcompatibilitics, the
problems encountered m the dispensing of
those ketones which arc used arc due usually
to insolubility or to the formation of eutectic
mixtures
Acetone (dimethyl ketone) is soluble m
water, alcohol, ether, chloroform and fixed
0
a
CHj— C— CH,
Oils Although It bos little application m the
compoundmg of prcscnptions, it is widely
used in pharmacy os a sohenL
Carboxylic Acids 317
Table 70 Solubilities op Some Monocarboxylic Acms
(Fatty Acid Series)
Acm
Solubility in Gm
PER 100 ML. OP
Water
Alcohol
Ether, etc
Formic acid
eo
eo
« eth , gly
Acetic acid
<o
so
eo eth
Propiomc acid
eo
eo
eo eth , chi
Butync acid
5 62
so
CO eth
Valeric acid
3 7‘»
CO
eo eth
Caproic acid
04
s
s eth
Capryhc acid
0 25>»®
s
so eth , chi
Capnc acid
si s
s
s eth.
Launc acid
1
13421
V s eth
Mynstic acid
1
44.921
s elh , chi
Palmitic acid
1
9320
s eth
Steonc acid
00342^
25
V s eth , s cfal
eth. = ether
chi s= chloroform
gly =glycena
Camphor is almost insoluble m water
(approx. 0 1 Gm per 100 ml ), but it is veiy
solume m alcohol, ether, chloroform, ben-
zene and acetone Incompatibibties of a sola-
0 ’°
bility nature usually are due to the addiuon
of water to alcoholic solutions of camphor,
m which case the camphor is precipitated
Camphor may also be precipitated fiom cam-
phor water by the salung-out effect of high
concentrations of water soluble salts Cam-
phor forms soft masses or hquids when tntu-
rated with chloral hydrate, phenol, menthol,
thymol and many other substances The
liquefaction causes little difficulty m omt-
ments but may be tioublesome m external
dustmg powders
CARBOXYLIC ACIDS
Mosocarboxylic Acids (Fatty Acid
Series)
SolubUity. The monobasic carboxylic acids
have approximately the same limits of solu-
bihty in water as the alcohols The oxygen-
hydrogen bonds of these acids are not polar
enough to allow them to dissociate to a great
enough degree to be solvated by water
through an acid base reaction- Therrforc, the
lower members of this senes are soluble in
water due to their ability to hydrogen-bond
with water As the alkyl cham is mcreased,
the solubilizing influence of the carboxyl
group IS not sufficient to overcome the sol-
vent-solvent interacuon of water, and the
molecule becomes insoluble
Although tbe monocaiboxylic acids are
weak acK^, they form water soluble ionized
salts by reaction with alkah hydroxides, car-
bonates and bicaibonates The aiLab sidts of
tbe water msoluble acids thus become soluble
m water through an lon-dipole mteraction
Hie alkali salts of the higher members of this
senes (Cio and up) ore capable of lowering
surface tension and are called soaps When
aqueous solutions of these water-soluble salts
are acidifled!, the free acid separates ouL AU
metals, other than the alkali metals, form
water insoluble salts with these higher acids
The monocorboxylic acids are soluble in
alcohol because of the ability of the two sub-
stances to hydrogen bond These aads have
low dissociation constants and low dielectnc
constants, and are soluble m ether and other
weakly polar solvents
Chemistry. The substitution of aadic (elec-
trophilic) groups for hydrogen in vanous
t p
CH ^"<
parts of the molecule profoundly affects the
aadity of tbe compound. The acidic group
IS an electron acceptor and draws electrons
toward iL This inductive effect causes a de-
318 Incompahbilitiet of Organic Compounds
Table 71 Dissooation Covstants op
Some Mosocarboxylic Acids and
Some Chlorinated Derivatives
Agio
K.
Temp
CC)
Formic acid
1 76 X 10-*
IS
Acetic acid
1 75 X 10-»
25
Propiomc acid
1 4 X 10-*
25
ChJoroacctic acid
J 4X 10-*
25
Dichloroacctic acid
5 X 10-2
25
Trichloroacetic acid
2X 10-1
13
o-Chlorpropionic acid
i 47 X 10-*
25
/3-ChIorpropioaic acid
8 59 X 10-»
25
creased electron density on the carbon atom
of the carboxjl group The electron pair of
the ox)gcn h>drogen bond, in turn, is held
more closely to the oxygen and the proton rs
held less hnnly Therefore, the acidic strength
IS increased, as is observed by the increased
dissociation constants in compounds with
this type of substitution (Table 71) This
effect is most pronounced when the substi*
tuUon of an acidic group for a hydrogen talies
place on the a carlxn atom and is diminished
mark.cdly the more remote the substitution
becomes Because of the ability of electro*
philic groups to withdraw electrons, the su^
stituuon of these groups on the o-carbon atom
not only increases the acidity, but also has a
loosening effect on the carboxyl group,
thereby causing an increased tendency to
dccarwxylate
When a hydrogen is replaced with a sub*
stituent that releases electrons, the opposite
effect IS observed Thus, when a methyl group
replaces a hydrogen of acetic acid, the mduc*
live c^cct IS in tlic opposile direction and a
slightly increased electron density m the car'
boxyl group results The proton now is held
more {irmly, and the acid strength is de*
creased as is indicated by the decreased dis-
sociation constant (Table 71 )
CH,-c'^OH + N«HCO, — ►CH,-C-ONo+KjO + CO^
0 0
// // /
Z CH,-C-OH +N9jC0, *2CM,-C-OK8+HjO + COj
All of the common metal salts of acetic
acid arc soluble m water, with the exception
of the Sliver and the mercurous salts, which
arc only sparingly soluble The acetates
readily hydrolyze m aqueous solution, with
the formation of basic salts of the metal
With acetates other than alkali salts, the basic
metal salt which is formed is usually less solu*
ble than the parent compound, and mcom-
patibihaes may result Similar incompatibili-
ties are observed when alkali acetates are
dispensed in aqueous solution with soluble
morgamc salts other than those of the alkali
met^ For example, a dark red color is ob-
served m solutions contaming the acetate ion
when soluble feme salts arc added This color
IS the result of the formation of feme ace*
rate, which then hydrolyzes and forms col*
loidal feme hydroxide The red feme hy*
droxidc 1 $ aggrecated and preapitated on
heating
The other lower members of this fatty acid
senes, such as propiomc, butync and valcnc
acids, are similar to acetic acid in their reac-
tions but seldom are used as such m medicine
Oleic acid (CuHjaCOOH) illustrates the
effect of an increase in the alkyl portion of
the molecule in decreasing the water solu-
bility This acid is insoluble m water, but it
IS soluble in alcohol and ether The alkah
metal salts of oleic acid arc soluble in water
due to the loo-dipoIc interaction between the
solute and the solvent On aadiffcation of
aqueous solutions ajntainmg soluble oleates,
the original water-insoluble oleic acid sepa-
rates out Soluble heavy metal salts give nse
to incompatibilities because of the formation
of the insoluble olcatc through double dccom
position reactions Since oleic acid is tiasalU'
CH ,-i— c H ^ c 0 H
Incompatibility. Acetic acid is soluble in
water, alcohol and ether It is a stronger acid
than carbonic acid, thereby causing the liber-
ation of CO] from carbonates and bicorbon-
ates m aqueous solution [acetic and =
1 75 X 10“*, carbonic acid K* = 35 X
10“^ (firstbjdrogcn)!
z — QNfl +(CH,- coo),p& -
Sodium Lead
Oleau Acetate
acHj-c-oNfl •KC,^„coo^ n
Sodium L e ad Oleata
Acetate (uuolubU)
i
Carboxylic Acids 319
Table 72 Solubilities of Some Polycarboxylic Acids
Acid
SOLimiLITY IN Gm
PER 100 ML OF
Water
Alcohol
Ether, etc
Oxalic acid
9.5
237
1 37 elh , i chi , pet eth , bz
Succinic acid
6 8»
0 3 eth , 1 bz., chi
Tartanc acid
13920
19 85“
04 eth.
Citnc acid
133
116“
Z26 eth
bz z= benzene
chi = chloroform
eih aether
peL elh = petroleum ether
Table 73 Dissociation Constants of Some Polycarboxylic Acids
K. K,
(First (Second
Acid
Hydrogen)
Temp
Hydrogen)
Temp
Oxalic acid
6.5 X 10-2
25
6 1 X 10-®
25
Succmic acid
6 6 X 10-«
25
28 X 10-*
25
Maleic acid
1 5 X 10-2
25
26X10-^
25
Fumanc acid
1 X 10-2
25
3 X 10-5
25
Tartanc acid
1 I X 10-2
25
69X10-'*
25
Citnc acid
8 4 X I0-<
25
18X10-®
(3rdH4x l0-«)
rated, it absorbs iodine by addition across ibe
double bond
The higher members of this senes such as
stcanc (Cl HmCOOH), palimuc (CwHai-
COOH) and mynstic acids (CisHj COOH)
are similar to oleic acid m their reactions
with the exception that they are all saturated
and do not absorb lodme In aqueous solu-
tions, the sodium salts of steanc and palmitic
acids have a tendency to gel, the potassium
salts exhibit a lesser tendency toward gel-
formation
Trichloroacetic acid (CCU — COOH)
IS a much stronger acid than acetic acid, m
fact, it approaches the acidic strength of the
mmeral acids This is due to the presence of
the 3 chlonne atoms which replace the 3
hydrogens on the o-carbon atom Since the
chlonne is an electron acceptor (electro-
philic), It tends to withdraw electrons from
the carboxyl group, thus causing the electron
pair of the oxygen hydrogen bond to be held
more closely to the oxygen This weakens the
oj^gen hydrogen bond to such an extent that
the hydrogen is held loosely and the com-
pound readily dissociates Tnchloroacetic
acid is very soluble m water m spue of its
mcreased molecular weight (each chlonne
bemg roughly equivalent to 3 carbon atoms)
The molecular weight of tnchloroacetic acid
(163 40) hes between that of pelargonic
(J58 24) and capnc (172 26) acids, both
of which are water insoluble Therefore, it is
obvious that the solubihty of tnchloroacetic
acid m water is not a matter of association,
as IS the case with acetic acid, but anses from
the fact that trichloroacebc acid readily dis
sociates by givmg up its proton to the more
basic compound, water Water dissolves the
acid through an acid base reaction, whereby
the water ruptures the covalent bond and pro-
duces ionization.
+ H SOS H — *
** 0 H
CCI,-O-0 + H SOS H
Tnchloroacetic acid is incompatible with
alkali salts of many weakly acidic substances
which arc water insoluble m the free state —
e g , soaps, phenates, etc. Being a strong acid.
It coagulates proteins (albumm,gelaun, etc.)
CCI,— C-OSH
320 Incompatibilities of Organic Compounds
and has a corrosive action on the sbn Be-
cause of this latter property, sometimes it is
used to remove warts and corns
Dicarboxyuc Acids
As has already been pomted out in the
chapter on solubiliucs, the intcrmolecular
forces existing in organic compounds play an
important role m the physical state and prop-
erties of the compound These compounds,
possessing strong dipoles, have high mter-
molecular cohesive forces due to the attrac-
tion of the positive end of a dipole in one
molecule for the negative end of a dipole tn
anoilicr molecule
Solubiiit), The dissolution of these acids
m the inert solvent, water, necessitates the
overcoming of the cohesive forces Oxalic
acid, possessing high mtcrmolecular forces,
exists as a solid and is less watcr-sotubte
than acetic acid, which is a liquid
Chcmistrj. The dissociation constants of
the dicarboxylie acids show the effect of the
additional carboxyl group m the molecule
Oxalic and acetic acids arc intcresling m this
respect, and it is observed that oxalic acid is
the much stronger acid of the two The addi-
tional carboxyl group attracts electrons so
that the hydrogen on the other carboxyl group
IS held less flntily and dissociates more
readily The dissociation constant for the sec-
ond hydrogen is reduced greatly by virtue of
the fact (hat, after the dissociation of the first
hydrogen, (hat carboxyl group then bears a
negative charge and repels electrons The hy-
drogen of the second carboxyl group is thus
held more firmly, as is shown by its dissocia-
tion constant (see Table 73) The more re-
motely the carboxyl groups are spaced from
each other m the molecule, the less prommeot
this mductivc cfTect becomes (see succuuc
acid. Table 73)
Cis trans isomcnsm also plays an impor-
tant part m detemumng the acidity in the uo-
saturated dicarboxylie acids When the car-
boxyl groups are dose to each other in space
(CIS form) , the mductivc cllect is greater than
when they arc farther apart (trans form) (see
maleic and fumaric acids, Table 73)
Hydroxy-polycarboxylic Acids
These acids are solids for the same reasons
as listed for the dicarboxylie acids In phar-
macy, these acids are represented by tartanc
and citnc acids
Solubility. These are weak acids and are
soluble m water because they contain a large
number of functional —OH groups relative
to their molecular weight They are soluble
m water because of their ability to hydrogen-
bond with the solvent The salts of the alkali
metals are water-soluble, but the normal salts
of most other metals arc insoluble
Incompatibility. Tartaric acid (dihy-
droxysuccmic acid) is a weak acid but it is
soluble m water, smee it is capable of asso-
ciation with water The normal alkah metal
COOH
I
CHOH
CHOH
COOH
salts of tartanc acid are soluble m water,
most other metals form water-msoluble salts
However, the bitartrates of potassium and
ammonium arc only slightly soluble A pre-
cipitate of potassium bitaitrate is often ob-
tamed m solutions containing soluble po-
tassium salts and tartanc acid Aci<^ also
prccipualc potassium bitarliale from solu-
tion contammg potassium-sodium tartrate
(Rochelle salt, IWaC<H 40 e) In the pres-
ence of strong oxidizing agents, tartanc aad
IS oxidized to oxalic acid Inasmuch as it is
a weak reduemg agent, tananc acid is capa-
ble of reduemg soluble silver and mcrcunc
salts, the reaction is accelerated with heat
Qtric acid is a water-soluble compound,
smee It possesses a large number of —OH
groups relative to its molecular weight It
CH,- COOH
HO-C-COOH
CHj-COOH
yields water-soluble salts with the alkah
metals, iron, magnesium, aluminum and cop-
per Many of the normal salts of other metals
Carbo}cyl>c Acids 321
Table 74 Solubilities of Some Aromatic Carboxylic Acids
Solubility IN Gm per 100 ml op
Aero
Water
Alcohol
Ether, etc
Acetylsalicylic acid
0 25
200
357 eth 59chl,v si s bz.
Benzoic acid
0271®
47 12“
40 eth., s chi , CCI 4 me al
Gallic acid
1 1623
33 0>«>
27 22»
2 5 eth , s gly
Salicylic acid
0 1820
39
50 Seth ,s chi
Tannic acid
285 7
V s
100 gly . v s acet . almost 1 eth , cbl ,
pet eth bz.
aceL = acetone
eih. = ether
me al methyl alcohol
bz. zz benzene
citZ. = chiorofona
gly = ^ycena
peL eth zz petroleum ether
are water insoluble, but the aad salts are usu-
ally soluble due to the free —OH groups
Since the alkali atrates are so extremely
water soluble, they are capable of salting out
alcohol from hydioalcohohc solutions This
gives rise to some mcompatibilities when con-
centrated solutions of tne alkali citrates are
mixed with alcoholic solutions such as elixirs,
tmctures, etc
The sodium, potassium and ammonium
atrates precipitate alkaloids from aqueous
solution m which they are present m the fonn
of their mineral acid salts The alkali citrates
yield solutions bavmg an alkabne reaction
and, m the type of mcompatibiliQr stated
above, the alkaloids are precipitated in their
free form due to the elevated pH (see Chap
4) The adjustment of the pH or the addi-
tion of alcohol to solubilize the precipitated
free alkaloid will overcome this type of in-
compatibility
Sodium, potassium or ammomum atrate
revents the preapitation of calcium, iron,
ismuth, lead and other salts from alkaline
solutions by forming chelates with these
metals which are water soluble
Sodium and potassium citrates often are
listed as solubilizing agents for acetybahcylic,
benzoic and salicylic acids The alkali citrates
promote the solubility of these compounds in
0
0
e?0M
CM. ^OM
1 V
3 frVeH +
OC-C-OM
'»M0C-C-0M
1 9
L,-C-0I«
1 #
CHfC CM
Salicylic
Sodium
Sodium
Citric
Acid
Curaie
Sahcylaie
Acid
t^t•alu
(water
(wsier
(water
uuoluble)
soluble)
soluble)
soluble)
aqueous solution through the formation of
the water soluble, ionized sodium or potas-
sium salts The resultmg acid atrate or citnc
aad IS also soluble
Aromatic Carboxylic Acros
Solubility. In considering the effect of the
aromatic nucleus on water solubility, we find
that the phenyl group is equivalent to m-
creasmg &e alkyl group m the normal ah-
pbatic senes by approximately 4 carbon
atoms ^ This increase in molecular i^eight
without an accompanymg increase m hydro-
philic groups greatly decreases the water solu-
bili^ Thus, benzoic acid, which may be
taken as a representative example of the
group, IS water-insoluble from the practical
standpoint of the pharmacist
The water insoluble members of this group
of acids are soluble in dilute alkali solutions,
since tb^ are sufficiently acidic to form
water-soluble ionized salts The salts denved
from the alkaline earth metals are much less
soluble than the salts of the nllfali metals
Most other metals form salts nhich are still
less soluble IncompatibiUues are encoun-
tered when the soluble alkali metal salts of
these acids are dispensed in an aqueous solu-
tion omtaming soluble salts of other metals
In this case, double decomposition occurs
and the water insoluble salts of the aromatic
carboxylic acids are precipitated Aqueous
solutions of the soluble alkali metal salts
yield the bee acids on admixture with acidic
solutions
Chemistry. The carboxyl group attached
to the benzene nng is an aadic (electrophilic)
322 Incompotibilillef of Orgonic Compounds
Table 75 Dissooatiov Constants of
Some Aromatic Carboxylic Acids
Temp
Acid
K,
(‘C.)
Dcnzoic aad
67 X 10-»
25
Salicylic acid
1 06 X 10-«
25
group and tends to withdraw electrons from
Uic aromatic nucleus This causes an area of
low electron density in the ortho and the para
positions Acidic reagents (electron accep-
tors) thus react at the meta position, whereas
basic reagents (electron donors) react at the
ortho and the para positions
Benzoic acid is practically insoluble m
water but is soluble in alcohol, fixed oils and
dilute alkali solutions In aqueous solution.
sodium benzoate yields precipitates with the
soluble salts of lead, mercury, iron, etc , due
to the formation of the water insoluble ben-
zoates of ilicsc metals The additioa of aetds
to aqueous solutions of sodium benzoate pre-
cipitates free benzoic acid Many references
list bcnzoic acid as being soluble m solu-
tions of alhah citrates or acetates This is
uivaicnt to dissolving benzoic acid in a
utc alkali solution. The water-soluble
ionized salt of the acid is formed, and the
resulting acid citrate, citric acid or acetic acid
remains soluble
Salicylic acid (onhobjdroxybcnzoic
acid) is insoluble m water from tlic prac-
tical standpomt of the pharmacist but is solu-
ble m alconol and dilute solutions of alkahes
In dilute aqueous alkali, it forms a water-
soluble ionized salt From the conventional
method of writing the structural formula for
saheyhe acid, it would appear that this acid
should be more water-soluble than actual
practice shows it to be That is, the presence
of two hydrophile groups for its molecular
weight would seem to indicate watcr-solu-
bility The low watcr-soIubility may be cx-
ptamed on the basis that it undergoes chela-
tion, thereby tying up the polar groups which
promote water-solubility
Free salicyhc acid is precipitated wrhen
aqueous solutions of sodium salicylate are
acidified Sodium sal]C}Iate causes mcom-
palibihucs when it is added to aqueous solu-
tions contauuDg soluble alkaloidal salts If,
for example, sodium salic) Iste and the hydro-
chloride salt of an alkaloid are dispensed to-
gether in aqueous solution, salicyhc acid and
the free alkaloid wiU precipitate This tyM
of incompaiibJjty often can be overcome by
the addiuon of alcohol to solubilize the free
acid and the alkaloid, provided that they are
not present m such large quanutics as to
make this procedure impossible or uode-
simblc
Aqueous solutions of sodium salicylate be-
come colored as the result of oxidation by
atmosphenc oxjgcn The color is due to the
conversion of the phenol to colored qumoid
oxidation products Air oxidation can
be prevented by the addition of 0 1 per cent
sodium bisulfite, sodium sulfite, sodium thio-
sulfate or other antioxidants The presence of
oxidizing agents in the solution, of course,
greatly accelerates the above reaction.
The salicjlates yield color reactions with
feme chlondc and copper salts “ The usual
eutectic mixtures are encountered when sah-
qIic aad is triturated with phenols, acids and
alcohols
Acetylsalicylic acid (aspinn) is pracu-
cally insoluble m water ( I Gm, per 400 ml )
but IS soluble in alcohol (1 Gm, per 5 ml )
and dilute aqueous alkali In alkaline solu-
tion, It forms the water-soluble ionized salL
Carboxylic Acids 323
In general, ace^Isalicyhc acid should not be
dispensed m aqueous solution since it under-
goes hydrolysis to yield acetic and salicylic
acids However, if an aqueous preparation
of aspinn such as is requested occasionally
by pediatricians is absolutely necessary, an
aqueous suspension can be prepared Ac-
cording to Its hydrolysis rate,** aspinn has
a half life of approiumately 20 days at pH
2 99 Thus, the aspinn can be suspended in
an aad vehicle such as atnc acid syrup and
remain sufficiently stable for a short period
of use Heat, acids and alkalies all hasten the
rate of hydroljsis of aspinxL After hydrolysis,
the liberated salicylic acid or salicylate ions
yield the typical color reactions with feme
salts See Chapter 2 for a discussion of the
kinetics of drug decomposition, the calcula-
tion of the rate constant and the balf-life
C-OH Q C-OH
OH + CHj-C-OH
The acetate and citrate salts of the alkali
metals have previously been recommended
C-OH 0
Acetylsalicylic
Acid
(nater
insoluble)
CH,-C-0No
1 0
-t- HOC-C-ONo— *
\ /?
CHj-C-ONQ
bodium
Citrate
(water
soluble)
O
o ^
// CHr-c-oH
r “'‘8 1
^y-0-C-CM,+ HO-C-C-OH
I I O
I //
CH,-C-OB
OUK
Add
(water
soluble)
Sodium
Acelylsalicylale
(water
soluble)
as solubilizmg agents for aceylsalicylic acid
m aqueous solutions, but this is also a ques-
tionable practice, smee hydrolysis still takes
place These salts yield alkiilme solutions
and form the water-soluble sodium acetyl-
sahcylate The acid citrate or free atnc and
acetic acids formed m the reaction are, of
course, also water-soluble
Acetylsahcylic acid is a stronger acid than
carbonic aad and effervesces with carbonates
and bicarbonates, liberating carbon dioxide
Aspinn forms soft masses when tnturated
with acetanilid, acetophenetidm, ammop^-rme,
antipyrme, etc
Probenecid (Benemid, p-(dipropyIsul-
famyl)benzoic acid) can be classi&ed both as
an aromatic carboxylic aad and as a sulfon-
amide type compound It is nearly insoluble
m water and dilute acids but soluble m alco-
hol, acetone, chloroform and dilute alkabes
CHj (jHj
CH2 ch,
I ' I “
CH, CH]
In medicme it is emp]o)ed as a uncosunc
agent m the treatment of gout and is used to
prolong the activity of penicillin, p amino-
saheyhe aad and phenolsulfoopbthalem m
the body
Tannic acid (tanmn, gallotannic acid) is
a complex and heterogeneous group of as-
stnngent plant prmaples m which one or
more of the hydroxyl groups of glucose are
eslcnfied with either gallic [CeH 2 (OH)a-
COOHl or digallic [HOOCCeH 2 (OH)s-
0C0C9H2(0H)3] acid ^ Tanmc acid is very
soluble m water, alcohol, gl)ceTm and ace-
tone The presence of many —OH groups m
its molecule, which enables this acid to hy-
drogen bond with other — OH-contaimog
compounds such as alcohol and water, ex-
plains Its great solubility in these solvents
The alkali metal salts of lanme aad are
324 incompolibilities of Orgonic Compounds
Table 76 A Comparison of tiie Water-
Solubility OF Some Esters and Alcohols
Compound
Solubility im
Gm per 100
ML QPHsO
Esters
Methyl acetate
s.
Ethyl acetate
8 62«
Propyl acetate
1 89W
Alcohols
Propyl
<o
Butyl
7524
Amyl
2 . 72 a
water-soluble, but the salts of many other
metals such as lead, tin, copper and iroa are
water insoluble The feme salts yield the
t}'p]cal blue black coloration and precipitate
with taniuc acid This is due to the oxidation
of the toanic aad by the iron The presence
of mineral aads and alkali citrates tends to
present this reaction with the feme salts The
oxidation potential of iron is reduced by acid
With the alkali citrates, a Fe* citrate
complex IS formed which also reduces the
oxidation potential of the iron
Tannic acid precipitates practically all al-
kaloids from aqueous solution, but the pre-
apitatc rcdissoUcs on the addition of alco-
hol Tannic acid reacts with proteins (gelatin,
pepsin, albumin, etc ) and prcapitates them
from aqueous solutions
In aqueous solution, taniuc acid is oxidized
and the solutions turn brown, presumably
due to the formation of qumoul oxidation
products of the phenolic compounds The
presence of oxidizing agents hastens the de-
composition Explosions may result from the
tnturation of tannic acid and strong oxidiz-
ing agents such as permanganates, iodine,
chlorates, etc , in the dry form
Tanmc acid also precipitates aotipynoe,
some neutral bitter principles, gl)cosiacs and
the plant gums (p 307)
ESTERS
An ester is an organic or inorgomc acid m
which the aad h)drogcn has been replaced
byanalk)lgroup
Esters Derived for Organic Aaos
O
II
Solubility. The esters of the R — C — O— R
type derived from alcohols and organic acids
ei^ibit approximately the same limits of solu-
bility m water as the alcohols Table 76 illus-
trates this similarity The introduction of
hydrophilic groups ( — OH, — MHz, etc )
into the ester molecule increases the polarity
and the water-solubility in the same manner
as It does m the case of the alcohols Ihere-
fore, waier-solubihty is augmented due to the
increased ability of these compounds to asso-
aate with water A comparison of glycerol
moQoacetate (monacetin, CH-OH — 42HOH
— CHjOOC— ^Hs) and propyl acetate, both
of which contom the same number of carbon
atoms, ailords a good example of the effect
of these groups in promoting water solubility
Glycerol monoacetate is very soluble in water,
whereas propyl acetate is much less soluble
(Table 76) As the length of the alkyl group
IS increased, there is a decrease in the Polar-
is and an accompanying decrease m the
water solubility Many of the esters arc solu-
ble m alcohol, but the alkyl group may be
mereased to such an extent that they become
practically insoluble m this solvent The fixed
oils (tnglyccndes), which contain the large
alky] group of the fatty acids, are a go^
example of this effect Inasmuch as the esters
arc relatively nonpolar compounds, they are
soluble in the other relatively nonpolar sol-
vents such as ether, chloroform, carbon tetra-
chlondc, etc.
tacompaUbilityv The estea axe acuUal
compounds which gradually hydrolyze m the
presence of water into tbcir corresponding
alcohols and acids The hydrolysis rate is in-
creased by both aads and alkabcs
Fats and Fixed Oils The fats and fixed
oils arc glyceiyl esters of fat^ acids Chem-
ically, there IS only a minor difference be-
tween fats and oils, the oils are liquid due to
the increased unsaturation of the fatty aads
These glycctyl esters arc rclauvtly nonpolar
compounds and are, therefore, insoluble m
water and alcohol, but arc soluble m other
nonpolar solvents such as ether, chloroform,
etc Castor oil is soluble m alcohol due to the
fact that the oil is composed mainly of the
Esters
325
tnglycende of ncmoleic acid [CHafCHj)®-
CHOHCH2CHCH(CH2 )iCOOH] which is
a h}droxy acid capable of associating with
the alcohol
Rancidity may develop m fats due to oxi-
dative, hydrolytic or ketonic degradation, but
usually It is attnbuted to the oxidative type
which IS induced and accelerated by the pres-
ence of air, light, heat, moisture and the pres-
ence of metal catalysts such as copper, zmc,
etc The products formed in the rancidifica-
tion of fats include aldehydes, ketones, lac-
tones, hydroxy acids, other acids of smaller
molecular weight than the parent acid, car-
bon dioxide and water ** Because of the
presence of free acids, rancid fats liberate
lodme from iodides Due to their unsatura-
tion, some fats and all oils absorb lodme at
their double bonds
Other mcompatibdities of a solubility na-
ture arise when oils are prescribed m prep-
arations containing water In such cases, one
must resort to the process of emulsihcation m
order to obtain a homogeneous preparation
The fats and the oils are saponified by
alkalies on long standing or with the aid of
heat All fixed oils contam a small amount
of free fatty acids which readily form metallic
salts, e g , lime water is utilixed in Calamme
Liniment to form the calcium soaps of the
free fatty acids of olive oil, which ^eo form
a water in-oil emulsion
Phenyl salicylate (salol) is practically
water msoluble Its molecular weight is too
great for the functional hydroxyl group to
carry into ai^ueous solution It is soluble in
alcohol and the less polar solvents, ether,
chloroform and fixed oEs The presence of
the phenobc — OH group enables phenyl
salicylate to form a water soluble ionized s^t
in dilute alkali solution, however, the aikah
accelerates its hydrolysis into salicylic aad
and phenol which then exist m the solution
as the soluble ionized salts
When phenyl salicylate is prescnbed m an
aqueous medium, either suspensions or emul-
sions can be prepared If a suspension is de-
sired, the particle size of the phenyl sahcylate
should first be reduced by suitable means and
the particles then suspended with the aid of
a viscosity-mducmg agent In the case of an
emulsion, the phenyl salicylate can be dis-
solved m a fixed oil (such as obve oil) and
the emulsion then prepared in the usual
manner
Phenyl salicylate forms soft masses or
liquids when tnturated with camphor, chloral
hydrate, tcrpm hydrate, thymol, phenol and
many other substances
Resorcinol monoacetate (Euresol) is a
water msoluble liquid which is soluble m
alcohol and most other orgamc solvents It
O-C-CH,
6 -
illustrates the effect of esterification m de-
creasmg the water solubilizmg properties of
the hydrophilic hydroxyl group Resorcmol
IS soluble m water smce it contains 2 phenobc
hydroxyl groups, and the ratio of the func-
tional — OH groups to the molecular weight
IS well withm the limits of water solubility
However, after eslenfication of one of the
—OH groups, the ability to associate with
water is greatly decreased, so that the result-
ing ratio of — OH groups to the molecular
weight falls beyond the limits of water solu-
bility Resorcinol monoacetate is soluble in
dilute solutions of alkali hydroxides but it is
rapidly hydrolyzed to resorcinol and acetic
acid ID this medium In alkaline solution,
resorcmol readily undergoes air oxidation to
colored decomposition products Oxidizmg
agents and heat accelerate this reaction.
Benzyl benzoate is msoluble m the more
polar solvents such as water and glycerm, but
IS soluble m alcohol and the less polar sol-
o
«>0 — CH
326 incompahbilitici of Organic Compounds
\ciiis ether and chlorofonn Since it is insolu-
ble in water, it is often used in the fonn of on
emulsion for external application in the treat-
ment of scabies The ofiicia! Benzyl Benzoate
Lotion of the contains oleic acid and
tncthanolanuoc which form the tnethanol-
anime soap as the emulsifying agent for the
benzyl benzoate.
Methylparaden and Propylparaben
Mcthylpirabcn (methyl parahydroxybenzo-
ate) and propylparaben (propyl parahy-
droxybenzoate) arc used for the preservation
OH OH
of pharmaceuUcal preparations which arc
subject to microbial aetcnoration The methyl
ester IS soluble to the extent of 1 Cm m 4C)0
ml of water, whereas the propyl ester is solu
ble only to the extent of 1 Cm m 2,000 ml
This illustrates the subsequent decrease m
water solubility which results when the alkyl
group IS increased m similar compounds
Inasmuch as both compounds conum the
hcnolic —OH group, they are readily solu-
Ic in dilute solutions of alkali hydroxides
but arc then hydiolzycd to the benzoate and
the corresponding alcohol These two com-
pounds arc also soluble in alcohol, ether and
iixcd oils
Glyceryl triacetate (inaccim) is mod-
Cfsiciy soiisbic in R’afer (7 17 Cm per }fX)
ml ) and is readily soluble in ether, alcohol
and other glyceryl esters (fats and fixed oils)
0
CH,-0-C-CH,
I “
CH-O-C-CH,
I ?
Glycctyl tnacctaic is not used as a therapeu-
tic agent but is mduded as a solvent m the
surgical antiseptic Chlorazodm Soluuon la
the presence of alkalies, it is hydrolyzed to
acetic acid and glycerol
Esters Derived from Inorganic Acids
The esters denved from alcohols and m-
oigaoic acids show varying chemical and
physical propcrucs The esters denved from
futne and nitrous acids are neutral, whereas
those esters denved from sullunc acid are
strong acids
Solubility. The nitnc and the nitrous acid
esters arc soluble in alcohol, but they are
msoluble m water The sulfuric aud esters
are strong acids due to the presence of the
coordinate sulfur-oxygen bonds which create
0
T
R-o-s— o:h
i
0
strong dipoles m the molecule The electron
pair of the oxygen hydrogen bond is held
more closely to the oxygen, and the com-
pound readily dissociates These compounds
are readily soluble in water, smcc they are
solvated through an acid base reaction In
alkaline soluuon, they form water-soluble
ionized salts
» ~ t fit
«-e-$-ei M ♦ HiwH — + mioim
© ~ 0
Esters denved from carbonic acid have
only a limited use in pharmacy They are usu-
ally wmer msoluble and soluble in alcohol
locompalibilily. The esters denved from
morgonic acids are readily hydrolyzed by
alkalies to yicfcf the parent afeohof and the
alkali metal salt of the aad
Nitrite Esters Nitrite Ethyl Ni-
trite Spint (spirit of nitrous ether, sweet spirit
of niter) is official in the N T The spint
gradually hydrolyzes m the presence of water,
CH3-CH2ONO
li^l and air, and liberates nitrous acid. The
nitrous acid present m the spint is capable
of liberatmg free iodine from iodides, oilro-
gen from ammonium salts and carbon dioxide
from carbonates and bicarbooates Gilor re-
actions arc observed with many aromauc
compounds such as acctomlid and aceto-
Esfers 327
NH^Bt + HNO TI2 NH^NO + HBl
f
NH^NOj— ♦ 2HjO + N,
phenetidin which yield yellow colors, anU-
pynne which exhibits a green color due to
the formation of nitrosoantipynne, and phe-
Eryihrityl Tetramtrate (Erythrol Tetra-
mtrate)
CH,-0-H0,
(
CH-O-NO,
I
CH,-0-N0,
AntipyTine Niirosoantipyrine
nohc substances widi which reddish brown
colors are produced The cause of the color
production is due to the substitution of the
—NO group into the molecule at centers of
high electron density As already explained
in the discussion of phenol, centers of high
electron density exist at the ortho and the
para positions The electroa*seekmg (electro*
philic) reagent thus reacts at these positions
Phenol
OH 0
0-0
More
Subte
Tauto
Qumone Nilfoso-
Moooxime phenol
(colored)
o Nitrosophenol
In alkaline solution, the ethyl mtnte is
rapidly hydrolyzed to ethyl alcohol and the
nitrite salt
Mannitol Hexanitrate
CHj-O-NOj
0,N-0-CH
' \
0,N-0-CH
I
CH-O-NO*
I
CH-O-NOa
CH2-0-N02
Pentaerythntol Tetramtrate (Peritrate)
OjN-O-CHj^ ^CHj-O-NOj
OjN-O-CHj/
The nitrate esters cause httle dithculty m
prescription practice because usually they are
dispensed m the dry tablet form They arc m>
soluble m water and soluble m alcohol In the
dry, undiluted form, they explode on percus-
sion and thus are marketed m the form of a
1 10 tnturation with lactose They are hy-
drolyzed readily by alkahes to the alcohol
and the nitrate salt
CMj-CHj-O-N so -t- NtOH—
Amyl nitrite (CH 3 — CHs— CHj— CHj—
CH 2 — O— NO) has similar potential mcom-
patibilities but it is always administered by
the mhalation method so that the dispensing
problems are elimmated
Nitrate Esters Glyceryl Trinitrate (Ni-
troglycerin, Glonoin)
CH,-0 — NO.
1
CH-0~H0,
CH,-0~N0,
CH.-O-NO. CH.OH
I I
CH-0 — NO, tSNgOH— » CHOH -tSNtNO,
I I
0^-0* NO, CH,OH
Glyceryl Ttmiirate Glycerol
Carbonate Esters Sal-ethyl carbonate
(carbomc acid ester of ethyl salicylate) is in-
soluble m water and dilute acids It is only
328
Jncompotibil lies of Organic Compound*
Table 77 Comparison of Boiling Points
AND Water Solubility of Some Alco*
HOLS, Ethers and Alkanes
Compound
B P
CC)
Solubility in
Gm per 100
ML. OP H-O
rl/cobols
Propyl
97 19
to
Butyl
1177
7 9-0
Amyl
138
2 722
Hexyl
157 2
0 59 0
Heptyl
176
0 09**
Etberr
Dimethyl
-23 65
3 700'*{em »)
Ethyl methyl
79
s
Diethyl
34 6
7 5-0
Methyl n butyl
703
V si s
Elhyl n butyl
91 4
L
Alkanes
Propane
Butane
-42 17
-0 6
U>-0 3
6 5>^(cm.»)
I5.iltcmn
Pentane
36 2
0 036‘«
Hexane
69 0
00138'**
Heptane
98 52
0 0052'* »
slightly soluble in alcohol but is soluble m
acetone and chloiofonn In the presence ol
alkalies, sal'etbyl carbonate is hydrolyrcd to
the salic)laie, ctb)l alcohol and carbonate
Ethyl Carbonate Elhyl Salicylate
Ethyl SaJicybte SoUium Salicylate
Creosote carbonate (Crcosotal) is a mu-
ture ol the carbonates of the constituents of
viood tar creosote It is a colorless to ycl-
loMish, clear, Mscid liquid This compound is
insoluble in water but is soluble in alcohol,
chloroform and fixed oils In the presence of
alkalies. It 1 $ h}dro!)'zcd to the carbonate
and various phenolic constituents of creosote
which arc, chiefly, guaiacol and creoso!
(mcth)lguaiacol)
Guaiacol Cicosol
ETHERS
Solubility. The ethers arc neutral, imrcac-
iivc, oiganic compounds When the boiling
points and the water solubility of ethers are
compared with those of alcohols of a com*
parable molecular weight, it is observed that
the subsutuuon of a nonpolar alkyl group for
the hydrogen of the —OH group causes a
great change m these physical constants This
type of substitution removes the hydrogen
Imnd function of the —OH group causmg
the ethers to resemble in some respects the
low boiling nonpolar hydrocarbons This also
results in a decreased tendency to associate
with water, which causes a decrease in their
water solubility The boibng points of the
ethers are also lower than those of alcohols
of comparable molecular weight, since, os
previously explained, the ethers, like the al-
kanes, are poorly associated, whereas the
alcohols ore highly associaied through hydro
geo bondmg
The ethers, being relatively nonpolar, are
insoluble m the highly polar solvents but arc
readily soluble in nonpolar solvents This
difference m solubilities is illustrated by a
comparison of the solubilities of the nonpolar
higher molecular weight hydrocarbons in
water, alcohol, ^yeerm, ether and chloro*
form Petrolatum and mineral oil may be
taken as examples of these higher molecular
weight hydrocarbons Both petrolatum and
mmeral oil arc insoluble m w atcr, alcohol and
glycerin but arc readily soluble m ether and
chlorofonm
Incompatibilily The ethers give nsc to
few incompatibilities since they arc very un-
rcactivc and are used but spanngly per se m
pttscnplions Ethers may be cleaved by
hydnodic acid to the corresponding alcohol
and alkyl iodide, but this reaction requires
drastic cooxliuons (rcfluxmg for 2 Iiours or
more), not normally encountered m manu-
faaunng procedures or pharmaceutical dis*
pensmg practice This reaction may be con-
sidered to be on electrophilic attack by the
hydrogen ion on the oxygen
Basic Nitrogen Confaining Compounds 329
R-CH^— <)— CHj-R— ►R-CHjOH+I + R-C^^
BASIC NITROGENCONTAINING
COMPOUNDS
HI
Amines
R-cf^ +r — ►R-cny:
Ether (diethyl ether, CHa— CHa— O—
CHa— CHa), although seldom used m the
actual filling of prescnptions, is used exten-
sively as a solvent m the phannaceutical in-
dustry Ether is an excellent extraction me-
dium, as It is generally a good solvent for most
organic compounds and dissolves only a very
few morgamc substances It is immiscible with
water and separates out as a discrete upper
layer Because of the high volatihty of ether.
It is removed easily by distillation from ex-
tracts at a temperature (34 6° C ) which
does not destroy the extracted prmciples
When ether is exposed to air and light for
long penods of time, it is oxidized to a non-
volatde peroxide which, on removal of the
solvent, becomes explosive when heated The
foUowmg substances have been identified ten-
tatively m the ether peroxide mixture
c-CH-o-m-CK, (cH.-eJ'l)
OH OH \
Dibydroxyelhyl Peroxide ElhylideDe Peroxide
Polymer
Ether is somewhat soluble in water (7 5
Gm per 100 ml ) and is soluble m strong
acids The solubility in acids is due to the
basic character of the oxygen The oxygen
possesses unshared electron pairs and is,
therefore, nucleophilic That is, it is capable
of donatmg electrons One pair of the un-
shared electrons thus coordinates with the
proton of the acid to produce a salt, as shown
m the following reaction
CHj-CHj-O — CHj-CHj - ,
The ammes are derivatives of ammonia
in which one, two or three of the hydrogens
are replaced by an aliyi group They are
designated as primary, secondary or tertiary
ammes, dependmg on the number of hydro-
gens which are replaced.
Solubility. The ammes have slightly higher
limits of solubihty m water than the alcohols
and other oi^gen-containing compounds
The lower a mm es are soluble m water due
to the presence of the unshared electron pair
on the nitrogen which makes it possible for
them to associate with water through hydro-
gen bonding
R
R ;n S —
•• 0
R H''
As the length of the alkyl cham is mcieased,
they lose £eir ability to compete with water
for a place m the association complex and
become water-msoluble
The water msoluble amines are soluble m
dilute acid solutions by virtue of the unshared
electron pair contamed on the mtrogen This
unshared electron pair coordinates with the
proton of the acid to form a water-soluble
ionized salt
Thus, the acid salts
and
- 1
l +
R
CH,-CH,-0-CH,-CH,
so^iT
R SNt H
= J
R
330 Incompatibilities of Organic Compounds
Tablets Comparisoh of the Water
Solubility of Some Aailves and
Alcohols
Compound
SoLUBILTTY IN
Gm per 100
ML. OF HjO
Mniine
Ethyl
09
Propyl
00
n Butyl
00
n Amyl
s
n Hexyl
si $
n Heptyl
si s
n Octyl
sLs
n Nonyl
si s
Ethyl
09
n Prop) 1
09
n Butyl
7920
n Amyl
2 7»
n Hexyl
0.59«
n Heptyl
0 09*»
n Octyl
1
n Konyl
t
of these basic niirogea compouods are water*
soluble, since the highly polar compound,
\satcr, IS able to rupture the lomc bonds and
solubilize the compounds through an ton*
dipole mechanism as it does m a similar
manner with NaG Due to their lomc nature,
these compounds are insoluble m the noo'
polar soUents such as ether, chloroform, ben-
zene. carbon tclrachlonde, etc.
The basic nitrogen in a pnmaiy, second-
ary or tertiary amine is capable of carrying
approximately 5 carbon atoms into aqueous
solution -• The rauo of the number of basic
nitrogen groups to the molecular weight of
the compound is operative m the same
manner as it applies m — OH-contaiomg
compounds, c g , n hczylanunc [CHj(CHj)#-
N!!*] IS only slightly soluble, whereas 1,6-
hcxancdiaminc [NHj(CHa)«NH 2 ] is very
soluble in water
The aliphatic amines are more basic than
ammonia, a fact which is borne out by tbev
dissociation constants In fact, tnmethyl*
amine is capable of displacing the weaker
base, ammonia.** However, when an aadic
group (electrophilic, electron acceptor) re-
places one or more of the hydrogens of am-
Table 79 Dissociation Constants (Kt)
DP Some Organic Bases
Base
Kb
Temp
Ammonium hydroxide
I 8 X 10“®
25
Metbylaminc
5X 10-*
25
DuDcthylamine
52X 10-«
25
Tnmethylamine
74X I0-»
25
Ethylamine
56X10-*
25
Diclhylamine
126X10-*
25
Tricthylamine
64 X I0-*
25
Pipendinc
1 6X 10-*
25
Pyndine
23 X 10-»
25
Aniline
46 X 10-**
25
Acetamide
3 1 X 10-*®
25
Acetanilid
4 1 X 10-**
40
moiua, a decrease in the basicity is obtained.
In this case, the electron pair bonding the
nitrogen to the acidic group is held more
closely to the acidic group, which, m turn,
causes the unshared electron pair of the nitro-
gen to be held more closely to the nitrogen
This then decreases the ability of the nitro-
gen to hydrogen-bond with water and, also,
decreases its ability to coordmate with the
proton of an acid in salt formation More
specifically, m Table 79, it may be observed
that aniline is much less basic than the alkyl-
substituted compounds The basic — NKs
(electron donor) group of aniline contains
an unshared pair of electrons which it can
share with the acidic (clcctrophihc) phenyl
group ** In the light of the preceding discus-
sion. It IS obvious that m the followmg struc-
ture the unshared electron pair of the nitro-
gen IS DO longer as readily available cither
for hydrogen bonding with water or for co-
ordinating with the proton of an acid to form
a salt The electronic shifts indicated m the
above structure also account for the high
relativity of the ortho and the para positions
with respect to electrophilic reagents The
onbo and the para positions arc centers of
hi^ electron density and react with reagents
which can accept electrons
Bquc Nitrogen Containing Compounds 331
TTie effect of decreasing water-soIubility by
substituent groups which replace one or more
hydrogens on the basic mtrogen is readily
borne out when benzylamme and amlme are
compared. Amlme is soluble m water to the
extent of 3 4 Gm per 100 ml , whereas
benzylamme, which contains one more car-
bon atom, IS miscible m all proportions The
mcreased solubility of benxylamme over
anUme m water is due to the fact that a
methylene group is mterposed between the
phenyl group and the ammo group so that
the ammo group m this case is not con-
jugated with unsaturation as m the case of
anifme This makes it impossible for the im-
shared electrons to shift and mcrease the
covalency between the mtrogen and the
aromatic nucleus
Other acidic groups when substituted for
a hydrogen of ammoma have a similar effect
in decreasmg the basicity of the mtrogen
The amides may be taken as an example In
this case, the shift of a pair of electrons from
the double bond between the carbon and the
oi^gen tends to cause an electron dehcicncy
on ^e carbon atom which, m turn, is satisflea
soluble m water, pelargonamide, CHj-
(CH2)7C0NH2 is insoluble) The lower
solubih^, m this case, is caused by the de-
creased availabihty of the unshared electron
pair of the mtrogen which is necessary for
hydrogen bondmg. A great decrease m the
basicity of the mtrogen also is observed (see
Table 79), and the aimdes have a neutral re-
action to dilute acid solution How ever,
Water insoluble amides are sufficiently basic
to dissolve m more concentrated acid solu-
tions
Actually, sufficient substitution of acidic
^oups for the hydrogens of ammoma may
progress to the pomt where the mtrogen no
longer retains its basic properties, and a re-
mammg hydrogen on the mtrogen becomes
acidic Suiffi IS the case with succimmide
and pbthalimide
by the shift of the unshared electron pair of
the mtrogen to cause an maease m the
covalency between the mtrogen and the
carbon Smce the oxygen has acquired a
share of an electron pair, it has become nega-
tively charged, and the mtrogen, havmg given
up a share of an electron pair, has become
positively charged If the molecule were com-
pletely polarized, it could be represented by
the followmg structure
Pblbalunide is practically msoluble in water
but dissolves readily m alkali. The sulfon-
amides and the ba^iturates, which will be
discussed m detail later m the chapter, are
also examples of mtrogen-contaimng com-
pounds with sufficiently strong acidic substi-
tution to cause a remainmg hydrogen to be-
come acidic
H-C = NH,
However, it exists in the more stable mtcr-
mediate form or hybrid between the conven-
tional structure and that shown above Al-
though water-solubility is not greatly affected
in the case of the amides derived from am-
moma, some decrease is observed (n-
nonylamme, CH 3 (CH 2 )iCH 2 NH 2 is shghdy
Alkaloids and Chemically Related
Compounds
In this chapter, the reader will observe
that alkaloids are not treated as a separate
class of compounds possessing mcompati-
bilities peculiar only to them but that the
discussion mcludes many chexmcally related
substances havmg similar incompatibiliUes.
Alkaloids. Because the substances of this
group differ so greatly m chemical composi-
332 Incompohbiljlies of Organic Compounds
uon, and since no one definition is sufficient
to include all the venous compounds, phar-
maceutical chemists have commonly resorted
to an cDumeraiion of some of the cbetnico]
and ph) steal characteristics of alkaloids m
lieu of a definition (S)nibetic substances
may have similar properties to those alka-
loids of vegetable or animat origin.) There-
fore, they have been stated to be white
oystalline substances — although a very few
ore colored (eg, berbenne), and some of
the oxygen free compounds are liquids (e g ,
nicolmc, coniine, etc } Most of the com-
pounds of this class react with alk)l halides
to give crystalline addition products They
give characteristic reactions with the com-
monly termed “alkalovdal reagents “ The free
alkaloids are usually water-msolublc but
soluble m dilute acid solutions and the or-
pnic solvents, whereas the alkaloidol salts
axe soluble m water and alcohol but insolu-
ble in the less polar organic solvents such as
ether, chloroform and the fixed oils (Table
80) However, m dctcrming the water-solu-
bility of the free base of al^oids and other
chemically related compounds, it must be
borne m mind that the basic nurogen is
capable of carrying approximately 5 carbon
atoms into solution Thus, such substances
as antipyrme, ommopynne, coiTcinc, etc , are
water soluble (p 330)
The nitrogen which is contained m the
molecule and which must be present m order
for these substances to be labeled os alka-
loids may occur m the form of pnmary,
secondary and tertiary (either alphatic or
cyclic) amines Other forms of nitrogen
combinations such as acid amides, acid
imidcs, cyanides, quartemary ammonium,
ammo imme, diaimno imino, imine and tn-
amme groups also may be present along with
the anunes m the alkaloid molecule -*
Although tlic presence of nitrogen is es-
scnual m alkaloids, they also contain many
other functional groups which contribute to
the ocUv ity of the compound from the chemi-
cal, the physical and the physiologic stand-
pomt These functional groups mdude pn-
moiy, secondary and tentary alcohols,
ketones, aldehydes, carboxylic acids, esters,
methyl ethers, methylene ethers and
phenols *•
Ciasstficauon of Some Alkaloids and Chenu-
0 iUy Related Compounds (.Basic N-Coniain-
ing Compounds)
h Alkylammc Group
A Primary Amine
1 Tuamine (2-ammoheptanc)
CHj-CH-CH-CH—CHg— CH-CHj
NHx
B Tertiary Amines (Diracthylcthyl-
ammo group)
1 Diphenh) dranune drochlonde
(Benadryl Hydrochloride, /J-di-
racihylammocthyl bcnzhydiyl ether
hydrochlondc)
2 Tripelennamine Hydrochloride
(Pynbcnzaminc, pyndylbenzyl-di-
ractbylcihylcncdiamme hydrochlo-
ride)
3 Thenylpyramine Hydrochloride
(Histadyl, Thcnylcnc, N,N-diracthyl-
N' (2 lhcnyl)-N' (2 pyridyl)-cth)l-
cncdiaminc hydrochloride)
II. PbenylalLylammc Group
1 Amphetamine (Benzedrine, 1-phcn-
jI-2 ammopropanc)
Basic Nitrogen-Coniaining Compounds 333
Parednne (p-hydroxy-l-phenyI-2-am»
mo-propane)
2 Methamphetamine Hydrochloride
(Desoxyephednne Hydrochlonde; 1-
phenyI-2-methyIammopropane)
O CHj-ch~ch 3 9 Phenylpropanolamine (Propadnne; !•
NHCHj . HO phenyl-2-ammo-propanol-l )
3 Ephednne (l-phenyl-2-methylanime-
propanol-1 )
a CH^CH-GHj III. Diphenylalkylamiae Group
OH NHCH ^ Meihadon (Dolophme, 4,4-diphenyI-
* 6-dimethylammoheptanone-3)
rpYCH-CH-CH,
OH NHg
4. Epinephrine (Adrenalm, methylammo-
etbanolcatecbol)
I *
NHCH,
5 Eptnine (3,4-dihydroxyphcQyIethyl-
methylamine)
6 Phenylephrine Hydrochloride (Neo-
synephrme, a-hydroxy-/3-methylainmo-
3-hydroxy ethylbenzene hydrochlonde)
rV. AUmnoIamine Group
1. Triethanolamine
HO-CHg~CH,
HO-CHj-CHj-N
A- p-Aminobenzoic Acid Derivatives
1 Procaine Hydrochlonde (Novocam;
p-ammo-benzoyl dxethylammo-
etbanol hydrochlonde)
jOH NHCHj'HCI
7. Nethamine ( l-phenyl-2-raethyIcthyI-
ammo-propanol-I )
NH.
0
C-O-Cl^-CHj-N ‘HO
CH — CH-CH.
J \
OH CH,-N-C,H-
2. Butacaine Sulfate (But^n Sulfate;
p-ammo-benzoyl-dibutylammo-pro-
panol sulfate)
334 Incompotibililies of Organic Compounds
3 MonocaineH)droch!onde (p ^mmo^
bcnzo)] isobut)! ammrxthanol hy*
drochlonde)
NHt
4 Tetracaine H^drochtonde (Pooto-
camc hjdrochlondc, p butylanuoo-
bcQzo) 1-/3 dimcth} lammO'Cthanol
h) drochlonde)
N-CH,-C«f CH^CH,
Ci0-CH,-CVN^
5 Am)Uine Hydrochloride (Nacpoinc
H) drochlonde, mono-n*am>}-a[nmo-
cth)l*p ammo'bcnzoalc hydrochlo-
ndc)
> Hd
CH,- CH,- CH,- CH,-CK,
B BcNZoicAao Derivative
1 Intracaine Hydrochloride (Di-
cthoxin, /3'dicth)!animocih)l>p-ctb>
OX} benzoate h}drochIonde)
0 /VOS
C Tropic Acid DERivATfVB
1 Syntropan (tropic acid ester of 3>di*
ctbylammo-2,2-dimeihyl-l-propanol
phosphate)
CH, CH,-CH,
C-CH,-N
D Diphenylacetic Acid Derivative
1 Trasenime (diphcnylacct}ldicthyl*
amino^thanol hydrochloride)
-C-0-CH,-CH,-N • Hd
V. Pjnduic Group
I Pellettertne
2 Sparteine 5u!/aie
W.-W.-K CM, M--CH.-CM,
* » , 1*1 1 , »
Wj-CH-W-CM,-CH,
3 Coniine
C^CH,-CM,-CM,
VI. Pyndioe-PjTrolidiac Group
I Nicotine
04,- CM,
-CH CH,
N / *
I
CM,
VII. Condensed Pjpcndine'PjiTohdme
Group (Troploe)
! Atropine
Basic Nitrogen Containing Compounds
2 Homalropme Hydrobromide
CH,-CH — 0®” __
J N CH, y HBr
CH,-CH CH,
CH,-0
H-N-CH-CHf-CHj-CHj-N
CH, 'CH,-CH,
7 Eucupin (Isoamylhydrocupreine )
3 Scopolamine Hydrobromide
(Hyoscme)
,CH CH CH- 0 '
/T I I * ^
0 I N CH- CH — 0—C —
\l t * \
CH CH CH,
4 Cocaine
c
e
CH,— CH^— CH— C— 0— CH,
[ «-».
CHj— CH.^— CH,
VIII. Quinoline Group
1 Quimne
H
8 Oxy quinoline
OH
IX. Isoquioolme Group
1 Papaverine Hy drochloride
2 Morphine Sulfate
2 Quinidine Sulfate (Dextro isomer of
quimne)
3 Totaquine (Contains the total alka-
loids of cmchona)
4 Cinchonine Sulfate
3 Codeine
4 Ethylmorphine Hydrochloride
(Diomn)
5 Cinchonidme Sulfate (Levo isomer of
cmchomne)
6 Pamaquine [plasmochme, 6 methoxy-
8-(l-methyl-4-dietb)lamino) butyl-
ammoqumolme]
336 incompotibilities of Organic Compounds
5. Apomorphine Hydrochloride
6. Dihydromorphinone Hydrochloride
(Dtlaudid)
7. Dihydrocodeinone
(Mcrcodeinonc, Hycodao, Dicodid)
NaiorpkiM Hydrochloride
(NoUine H)drochloiide)
KCJ
9. Methyldihydromorphinone Hydroch!o~
ride (Mctopoo Hydrochloride)
X. Indole Group
1. Physosiigmine Sahcylaie (Eserme
salicylate)
it
(Protnioaal Suucture)
3. Ergoloxine
4. ErgonoMne Mdeaie
5. Ergotainine Tarxrate
Basic Nitrogen Containing Compounds 337
6 Reserpme
XI. Imidazole Groap
1 Pilocarpine Nitrate
rCH,-
2 Naphazobne Hydrochloride (Pnvme
Hydrochloride , 2 (naphthyl- ( T) -
methyl) imidazoUne hydrochlonde)
3 Histamine Phosphate (4 imi-
dazolylethylanune phosphate)
XIII Pipendme Group
1 Meperidine Hydrochloride (Demerol
Hydrochlonde, Isonipecame, Dol-
anthm, Pethidme, ethyl l-melhyM-
phenyl pipcndine-4-carboxylate hydro-
chlonde)
e
^-o-cvw,
I HO
CM,
XII. P}Tazole Group
I Antipynne (Phenazone, 1,5-dimethyI-
2 phenyl 3 pyrazolone)
2 Piperocaine Hydrochlonde (Mety-
came,benzoyl-7-(2 methylpipen-
dino) propanol hydrochlonde)
HCI
2 Aminopyrine (Amidopynne, Pyrami-
doQ, 1,5-dimelhyl 2 phenyl-4-
dunethylanuno-3 pyrazolone)
3 Surfacaine (Cyclomcthycame, p-cyc!o-
hej^lozybenzoyl-y-(2 methylpipen-
dmo) propanol hydrochlonde)
0
c-e-CMi-cM^cH,-
-5
338 Incompotib lilies of Organic Compounds
4 Dwtliane (Pipcnduiopropancdiol-di-
phcn)!urcihane h)drochiondc)
I 9
CH,-e-c— * ih-A
\IV. Amlioc Group
1 Phenacaine U)drochlonde (Holocainc,
cthcn>l p p'*diclhox)diphcn)]amtdinc
h)dr(^onde)
XViL FhcDOtbuizuie Group
1 Promethavne (10 (2 diracihylanimo*
prop)l)>phcnothiaziQc)
CH,
0-CH,-CH, 0-CHj-C«,
\V. Purine Group
1 Cfli7«He (I|3, 7 (nracthjlxanthuae)
1
o-c c-hC
I II >
CK,-M — c— n
2 Theophylline (i,3*dimcth)Uanthinc)
2 Promazine (10 (3 dimcthylammo-
propyl) phcnothiazmc)
I
CH^
I *
CH^
CH, CH,
CH,-N— C-O
I I
O-C C— K-M
I U
CH-N — C-
3 Chlorpromavne (Thorazine, 2-chlon>-
10 (3 duncthoyaminopropyl)*
phcnoihiazinc)
3 Theobromine (3,7-dimcih)Uaalhmc)
HN — c-o
I I
-C C-H — CM,
1 I > *
\>I. Guanidine Group
1 Chloroguamde Itydrochlonde
(Guanatol Iljdroclilondc, N^-p-
chloro-pheny] N. isopropyl
biguanide hydro^oridc)
1 ^
CHj— N-CH,
/CH,
CH HU
M,
Incompatibility. The alkaloids and chemt'
cally related compounds containing tnv'alcnt
nitrogen arc capable of forming ^^atcr solu-
Basic Nitrogen Containing Compounds 339
ble salts with acids The unshared electron
pair of the nitrogen coordinates with the
proton of the acid to form the correspondmg
water-soluble ionized salt IncompatibiUties
may thus result from attempts at dispensing
these water-soluble mmeral acid salts m an
aqueous medium havmg an alkalme reaction,
m which case the free base is precipitated,
provided that it is not sufficiently water-
soluble to remam m solution as such This is
perhaps the most frequently occtirrmg type
of mcompabbihty for this class of com-
pounds Included m the hst of compounds
which give an alkalme reaction m aqueous
solution are the soluble hydroxides, carbon-
ates, bicaibonates, the alkali citrates, tar-
trates, acetates, the sodium salts of bar-
biturates, the sodium salts of sulfonamides,
etc The foUowmg examples, while typical of
the alkaloids, also are applicable to the
chemically related synthetic compounds m-
cluded m the previous classification
sible means of conectmg these mcompati-
bilities*
1 Neutralization of the solution before
the addition of the min eral acid salt of the
basic N-contammg compound
2 Suspension of the insoluble precipitate
with the acid of acacia, tragacanth, Metho-
cel, etc
3 The addition of alcohol or other water-
juiscible solvents such as gl}cenn or propy-
lene glycol to solubilize the free base Of
these three methods, the last is most often
used by the pharmacist The addition of acid
to neutralize the alkaltnw solution may lead
possibly to other mcompatibilities, the use
of a suspending agent markedly changes the
physical charactenstics of the prescnption
and may not be desured by the physician,
whereas few physicians are averse to the ad-
dition of a small amount of alcohol for pre-
scnpUoDs intended for mtemal admimstra
tion Usually 10 to 35 per cent of alcohol
1 Alkaloidal salt (HCl) -I- NaOH free alkaloid + NaQ -i- H^O
water soluble) (water insoluble)
2 Alkaloidal salt (HCl) + sodium pbenobarbital -»free alkaloid -I- free pbenobarbital + NaCI
(water soluble) (water insoluble) (water insoluble)
3 Alkaloid salt (HQ) + sodium citrate -» free alkaloid + cilnc acid + NaCl
(water soluble) (water insoluble) (water soluble)
Other mcompatibiliues m the nature of
precipitant reactions, of course, would be
present when compounds of this class are
dispensed m an aqueous medium containing
any of the “alkaloidal reagents ” However,
this type IS not too frequent, smce ffiese
reagents are not employed commonly m pres-
ent-day prescribmg trends, althou^ tanmc
acid and tamun-containmg preparations are
occasionally a source of thfficulty The van-
ous lodme complexes are encountered even
less frequently, but it is to be remembered
that the presence of any substances which
will give nse to the formation of KafHgli)
(Mayer's reagent), Na2(Hgl4) or HaCHgli)
— or any of the other alkaloidal precipitants
— will cause precipitation.
These preapitation reactions are undesir-
able m prescriptions because a uniform
dosage cannot be ensured, and too large an
amount of the potent drug may be taken
la a smgle dose
Three methods of overcommg these pre-
cipitation rcrnmons are aften listed as a pos-
ts sufficient to dissolve the msoluble precipi-
tate m all of the above mcompatibihties
The esters of this class, which mclude the
local anesthetics such as Butacame, Laro-
came, Monocame, Naphthocame, procame,
Tetiacame, Tmocaine, Metycaine and Suria-
caine, the alkaloids atrophme, homatropme,
rescrpme, scopolamine, cocame and their
synthetic substitutes, Syntropan and Trasen-
tine, etc , undergo hydrolysis m aqueous me-
dium to the correspondmg alcohol and aad
from which they are derived. The rate of
hydrolysis (see Chap 4) is greatly acceler-
ated at pH's near neutr^ty or on the alka-
lme side and by the apphcation of heat, as
m stenlizmg If these substances are bufiered
on the acid side (pH 3 0 to 5 0), the sta-
bility of their aqueous soluuons is enhanced
greatly
As a general rule, it may be stated that
alkaloids are mcompatiblc with oxidizmg
agents Some substances such as epmepb-
nne, Epmme, Parednne, Neosyncphnne and
physostigmme are even oxidized quite readily
340 incompatibilitiei of Organic Compounds
Table 80 Solubilities of Some Alkaloii^ and Qiemically Related Synthetic
Compounds (Basic N*Containinc Compounds)
StoLUBILITY IN Cm per 100 MU OF
Water Alcohol Eihcr, etc
s s 1 cth
66 7 6 clh
1 Acclylchohoe chloride
2. Anunopjnne, U^P
3 Amphetamine (Benzednne)
4 AmphetammesulfatefBenaednneSuIfate)
5 Am)huie hydrochloride (Amjlcatoe)
6 Anljpynne
7 Aponmrphmc
8 Apomorphme hydrochloride
9 Atropine
10 Atropine sulfate
1 1 Benzalkomum chloride (Zephiran
Chloride)
12. Butacaine sulfate (Butyn)
13 Butyl aminobeozoate (Butesin)
14 CalTeioe
15 Carbachol
16 Chlorpromazine hydrochloride
17 Cinchonidine
I S Cinchonidine sulfate
19 Cmchooioe
20 Cinchonine sulfate
21 Cocaine
22. Cocaine hydrochloride
23 Codeine
24 Codeine phosphate
25 Codeine sulfate
26 Comme
27 Meperidine h) drochlonde ( Demerol
11) drochlonde)
23 Melhamphciamine (Desoxyephednoe)
29 Methamphetamine hydrochloride
(Elcsoxyepbednne Hydrochlonde)
30 Dihydromorphinone hydrochloride
(DJaudid)
31 Diotbane Hydrochlonde
32. Diphcnhydr^ine hydrochlonde
(Benadryl)
33 Ephednne
34 Ephednne hydrochlonde
35 Ephednne sulfate
36 Epincphrme
37 Epinephnne hydrochlonde
38 Epinine
39 Ergonosine (Ergomeinne)
40 Ergonovme maleate (Ergoirale)
41 Ergotamine
42. Ergotamine tartrate
43 Ergotoxine
44 Elthyl aminobcnzoate (Bcnzocatne,
Anesthesm)
45 Ethyl morphine hydrochloride (Dionm)
46 Eucupia (Isomylhydrocupreine)
si s
s
s cth
»
si s
1 etb
s
si s
1 eth
too
100
2 6 cth
si s
s
s cth
2
2 47
0 053 cth
0II«
68 5
56elh.64chl
260
27
0 05 etb, 016 chi
s
5
1 cth
100
S.
I eth , si s chL
000014
s
s eth , ch]
1J5»®
2 3>«
0 044 cth . 142chl
100
2
1 cth . chi
too
66 6
s chi . 1 cth
0019““
4 81
041 eth. s chi
154
I 37
0024 cth .0 I6chl
0 0272®
0 7952®
0 27 eth , s cbl
1J5‘»
17”
0 043 cth , 2 I chi
016»»
20»
26 3 cth ,s cbl
250«
38 4«
1 cth
0 83»
62 52®
8 0 eth , s chi
44 5»
0 3 82-
0 07 eth
3 3“
oi»
1 cth . chi
1 1
«
V si s eth
s
$1 s
1 cth
V si s
s
s eth
s
si s
I cth
33
sp 1
1 cth
sLs
a.
1 eth
s
s
1 . eth
$
s
5 cth , chi
33
7 14
I cth.
s
$ h
1 cth
0027”
si s.
1 cth , chi
s
s.
L eth.
U s
si s
si s.
si s.
sp s chL
2.77
83
1 Clh , chi.
shs
i
s clh ,ch]
02
02
V si s.
s b.
si s clh.
004
20
50 chi ,25 clh.
10
4
si 1 eth.,cbL
L
t.
t eth
Bauc Nitrogen Containing Compounds 34 1
Table 80 Solubilities of Some Alkaloids and Chemically Related Synthetic
Compounds (Basic N-Containing Compounds) (Continued)
Solubility IN Gm per 100 ml of
Water
Alcohol
Ether, etc
47 Chloroguamde bydrocblonde
(Guanatol Hydrochlonde)
sp s
s
1 etb
48 Histamine
s
sL s
49 Histamine phosphate
50 Homatropme hydrobromide
25
17 5»
33
0 23 chi . 1 eth
5 1 Intracame hydrochlonde (Diethoxm)
s
s
52 Methacboline cblonde (Mecholyl)
s
s
s chL
S3 Methadone hydro^londe
s
%
1 eth
54 Metycaine hydrochlonde
s
s
s chi , 1 eth
55 Monocame hydrochlonde
sp s
sl s
sl s chi , 1 eth
56 Morphine
003
0 39
0 02 eth , s cfal
57 Morphine sulfate
6 66
0 22
1 eth , cb!
58 Morphine hydrochlonde
5 72
2 38
1 eth , cbl
59 Nalorphine hydrochlonde (Nalline
Hydrochlonde)
s
61
V sl s cbl , 1 eth
60 Neostigmine bromide (Prosugmm
Bromide)
100
s
L eth
6 1 Neostigmine methylsulfate (Prostigrmn
Metbylsulfate)
10
s
1 eth
62 Phenylephnne hydrochlonde
(Neosyoephnne Hydrochlonde)
s.
s
I ctb
63 Nethamme hydrochlonde
70
14
s eth , cbl
64 Nicotine
$
s
65 Nicotine hydrochlonde
s
s
66 Oxyqumolme
L
s.
67 Oxyqumolme sulfate
68 Pamaquine naphthoate (Plasmochio)
S
s
s acet
69 Papaverine
V sl s
V s
0 39 eth
70 Papavenne hydrochlonde
2 7»»
s
1 eth
7 1 Parednne hydxobromidc
72 Pellelienne
X.
5
s
s eth , cbl
73 Pellelienne toonaie
04
5
sL s eth., 1 chi
74 Phemerol Cblonde
s
s
1 . eth
75 Phenacaine hydrochlonde (Holocainc)
s
1 eth
76 PhysosUgmme (Esenne)
sl 5
s
s eth , chi
77 PhysosUgmme salicylate (Esenne)
133
771
0 57 eth , s chi
78 Pilocarpine
s
s
sl s eth , s chi
79 Pilocarpine hydrochlonde
333
37“
1 eth , si s cbl
80 Pilocarpine nitrate
10“
1 eth , chi
8 1 Naphazohne hydrochlonde (Pnvine
Hydrochlonde)
s
s
V sL $ cbl , 1 eth
82 Procaine hydroeWonde (Novocain)
(00
3 33
si s chi , 1 eth
83 Pbcnylpropanolamme hydrochloride
(Propadnne Hydrochlonde)
s
s
I eth , chi
84 Quuune
154
73 8 eth , s chi
85 Quinine hydrochlonde
56“
166“
042 eth
86 Quimne dlhydrochlonde
166 6
103
V sl s eth , si s chi
87 Quuune bisulfate
11 1
5 36
0056 elh ,s chL
88 Quinine sulfate
014“
1 16“
sLs eth.
89 Quiiudtoe
005«
420
4 5 eth , s chi
90 Quinidine sulfate
1 0“
12
V si s eth , s cbl
91 Reserpme
105“
0 055
1 6 67 chi . s acids
92 Scopolamine (Hyoseme)
V s
V $ eth. s. chi
342 Incompotibilihes of Orgomc Compounds
Table SO SoLuettmcs of Softfs Alkaloids aso Chewcally Related SYNniETic
CoMPousDS (BasicN-Covtainino Compounds) iCotUtnued)
SOLUDIUTY IN GM
PER 100 ML. OP
Water
Alcohol
Ether, etc.
93 Scopolamine b)drobroinide
(H}osane H)<lrobromidc)
66 6^
6 3“
1 clh .0 13 chi
94. Sponcme
0404“
V s
V s. cth , s. chi
95 Sparteine sulfate
90.9“
33 3“
1 eth , chL
96 Strychnine
0016“
09
0018 cth,s.chl
97 Sir) chmne nitrate
2.4“
0 83
1 cth , 0 64 cbl
98 Suycbnine phosphate
3 33
si s.
1 cth
99 Sli)chiunc sulfate
3 2“
1 J“
1 cth ,s. chi
100 SurfacaiDC* (Cyclomclh)caine)
101 S}'ntropant
10 +
s
si s.
1 eth , cbl
102. Tctracame hydrochloride (PoDtocaine)
s
s
1 eth
103 Telractbylammonium chloride (Etamoo
Chlonde)
s
s
I cth
104 Then) Ipyramine hydrochloride
(Histad)l Thcn)leRe)
5
J
1 eth
105 Theobromine
003'*
0 023*'
si s eth
106 Theophylline
044'*
1 25
st s eth
107 Totaquine
1
s
s chL
103 Traseaiinet
109 Tnethanobiemne
$
s.
si s eth
110 'nipclennamineh)droch]ondc
(Pynbenzaniine)
s
1 Clh
HI Tuamine
si s
s
s cth cht
112. Tuanune sulfate
s
s
sp s cth
* As the h)tlfDchlonJe t As the phosphate t As the b)droch1orKle
by ihc oxygen of ihc atr Therefore, ao aoD-
oxidant such as sodium sulfite m a 0 1 per
cent concentration is added to prevent ^is
reaction and mamtam their stabUity These
compounds arc oxidized much more readily
in an alkaline solution than in an acid solu-
tion Thus, the use of buffers to maintain the
soluuon at the proper pH aids materially in
preventing their decomposition The use of
buffers to maintain the stability of these solu-
tions by preventing precipitation, b)drol)‘sis
and oxidation reactions and to make them
compatible with tissue fluids is of great im-
portance m ophthalmic solutions and solu-
tions mtended for application to the mucous
membranes of the respiratory tract
Sorenson s modiiic^ buffer s)stem at a pH
of 6 8 (ct^ual parts of an M/IS NaHsPOc
solution and Af/lS NaiHPOt solution =;
6 SI) has been recommended** as a buffer
for atropine, epfaednae, cucatropme, faoma-
iiopmc and pdocarpwc The United States
Pharmacopeia^* recommends a 1 9 per cent
bone aad solution for salts such as those of
cocamc, piperocaine, procamc and tctracame
Quaternary Ammonium Compounds
The drugs of this chemical class mclude
the parasympathomuncUc agents ace^Icbo-
line chlonde, methacfaolme cblonde, car-
bachot, neostigmine bromide, neostigmine
mcthykulfatc and bcozpyruuum bromide,
the parasympatholytic agents mcthanthelme
bromide, propantheline bromide, ontrcnyl,
tiyC)damol sulfate, and those possessmg both
paras)'mpalholytic and sjTnpathol)tic activ-
ity such as tctracthylammonmm chlonde,
bcxomcthonium bromide and hcxamcthonium
chloride The surface active and gcnmcidol
agents bcnzcihomum chloride, bcozalkooium
chlonde and cetylpyndinium chlonde also
belong to this chcmi^ class
Batic Nitrogen>Contaimng Compounds 343
r
■4-
CH,
CK,
CH,-N-CH,
CH,-CH,-N-CH£-CH,
Cl“
ifS ?
V*
CH,
CH,
Tetraethylammonium Chloride
(Eumon)
CHs CH3
CHj-N-CHj-lCHjl^-CHa-N -CH^
CHj L3
++
acr
Hexametbomum Chloride* [Esomid Chloride,
Hexametoa Cblonde, Merhium Otlande, Hex
ajsethylenebis (trunetbylammooium chlonde))
* Also avaOable as Hexametboiuum Bromide (Bis*
tnum Bromide)
Neostigmine Methyhullate (Pros*
tigmina Methylsulfate, dimethyl*
carbamic ester of 3 hydroxy*
phenyltrunethylammomum
methylsulfate)
Benzpyrimtim Bromide [Stigmonene Bromide,
1 Benzyl 3 (dimethylcaibamyloxy) pyridinium
bromide]
CH,-N-CH£-CHjj-0-C-CH, Cl'
CH,
Acetykholme Chloride
CH,-N — CH.-CH-O-C-CH, d”
• I * I *
CH, CH,
Methacbolme Chloride (acetyl 4
methylcboline chloride)
CH,
I *
CH,-N-CH,-
CH,
Methaaibehae Bromide (Baaihme Bromide, 4*
dgthylmethytom moahyl 9-'xaotheaecarboxylate
bromide)
Cartiachol (carbammoylcholine
c^nde)
Propaolhehae Bromide (Pro-Banthioe, d-duso*
propylmetbylamiooethyl 9 xantheoecarboxylaie
bromide)
Neostigmine Bromide (Pros*
Ugmine Bronude, dimethyl*
carbamic ester of 3 hydroxy*
p^nyl trimethylammooium
bromide)
Antreoyl [diethyl (2-hydraxyethyl) methylamm^
mum bromide a-phrayl-cyclobexaiieglycolatel
344 Incompalibilities of Organic ComiMuncis
Tricyclimol Sul/ato (Elorme Sulfate l-cyclobexyt
I pheoyi ^pyrrolijino-l propanol metbyUulfate)
Denaethoniuin Chlorule IPbernerol Chlorule, p-(2
methyl'4- 4^imeih)l penune-2) (phenoxy-cthoay
ethyl) 'Ounethyl-benrylartunoflium chloride]
CM, I*
R-M-CM,
a
R s • muiiure of alkyls
from CaIIi> (O Cmllar
Oeaulkomum Chloride
(Zcphiran Chloride al
kyldimeihylbeiuyUm
moQiurn chloride)
CetylpyTidmium Chloride
(Ceepryn)
Solubtlitj. The qualeroary ammoaium
salts arc denvcd from tertiary amines and an
alL}I halide In this reaction, the covalent
bond between the halogen and the carbon
atom of the all)l halide is broken m such a
manner that the halogen retains the electron
vthich uas contributed by the carbon atom
to the covalent bond The halogen thus re*
tarns Its stable octet, and the carbon atom
has lost an electron The halogen gams an
electron and becomes negatively charged
The alk)l radicid, having lost an electron, is
positively charged and accepts a slure of the
unshared electron pair of the mtrogen to
complete its octet. The nitrogen, havmg given
up a shore m on electron pair, becomes posi-
tively charged and the solid, water-soluble,
ionic salt IS formed as indicated below
Te(rul)cy) Ammonium Hatide
Base Strength The tetraalkylammo-
mum hydroxides contrast sharply with am-
momum hydroxide and the amme hydrates
in that they arc much stronger bases These
quaternary bases do not decompose with the
loss of water, as do the amine hydrates and
ammonium hydroxide, but dissociate to yield
a high concentration of the hydroxyl ion and
the tetraalkylammonium ion As is mdicated
by the following structure, the quaternary
ammonium bases are completely ionized and,
therefore, arc comparable in base strength
with the hydroxides of the alkali metals
Tt(rulk)luiUDe>fuum
Hydroitdo
Incompalibihly, These quaternary am-
momum salts contrast with the hydrobalide
salts of the amines m their behavior toward
alkalies They do not liberate the free amine
on reaction with alkali Although the follow-
ing reaction may be considered as taking
place, all of the substances present are com-
pletely ionized Alkalies, therefore, are not
a source of a solubility mcompatibdity with
the quaternary ammonium salts
The surface-active agents and germicidols
such as bcnzalkonium chlonde, cctylpy-
ndmtum chlonde and benzcthonium chlo-
nde are cationic agents and their germicidal
activity m aqueous solution is reduced greatly
by such amonic agents as soaps, sodium
lauiyl sulfate and diocyil sodium sulfosuc-
cinate This decreased activity is due to the
1
Aadtc Nitrogen Containing Compounds 345
coacervatioa which takes pl^ between op-
positely charged anionic and cationic agents
The parasympathonumetic agents of this
group are chemically similar but give nse to
few mcompatibilities, since their therapeutic
use does uot often mvolve admixture with
substances other than solutions to control
the pH, e g , neostigmme broimde and bone
aad.
ACIDIC NITROGEN-CONTAINING
COMPOUNDS
As explained m the discussion of the basic
mtrogen-contammg compounds, the nitrogen
may be sufficiently substituted with acidic
groups to weaken the nitrogen hydrogen bond
to such an extent that the remauung hydro-
gen becomes acidic The proton may then be
lost m basic solution with the formation of
the water soluble ionized salt (see p 331)
Sulfonamides
The sulfonamide drugs afford a good ex-
ample of the effect of this type of substitu
tion In this case, the sulfonyl group is suffi
ciently acidic to overcome the basicity of the
mtrogen An acidic group decreases the
basicity of a basic mtrogen m the same way
o«-s-*o
I
NH,
Siif angami dg (p-axmoobeozeoe
sulfooaoude)
Sulfapyndme (2 p-amiao-beazene
tulfoaaimiij3p}Tidi&e)
04— $— »0 S CH
KH---C^ CM
Sulfathmole (2-suUuuU&iidothuzole)
Sulfadiazine (2*sulfaniIainjdopyriniidine)
Sulfamerazme (2 sulfanilanudo-4>
methyl pyrimidine)
Sulfamethazine (2-suIfatulanudo-4 &-
dimethyl pyramdtne)
0 «— S-eo jiH
Sulfasuanidme (p-amino*
benzenesulfonylcuanidine)
Sulfisozizole (Gantn&in, 3 4-dimethyl
346 Incompotibilities of Organic Compounds
Sulfwiii}litia4iUoIe (J-ctiiyl 2-«uir&iuhaudo*
1 J 4-(hia4ltuotc)
Sulfuneiftoirpyrklujae (l-tulfanjlamido-
6-methot)p)rkJuine)
t:
p
SucctnyliulfAihiuole
(SulfoMaidine)
PhituJjUul/aihluote
{Sul/ubaMinc)
It mcrco&cs the aodity of an aud — that iSt
by withdnniog dectroos In the case of the
sulfonamides, the tn-o coordmately bonded
ox)gea atoms cause the sulfur atom to be*
corns dcctroQ*deficient. In an attempt to
satisfy this deficiency, the sulfur tends to
wuhi^w electrons from the nitrogen. This,
m turn, causes the pair of electrons bonding
the hydrogen to the mtrogen to be held more
closely to the mtiogen so that the hydrogen
becomes bound loosely and is given up
readily m basic solution to form the water-
soluble ionized salt. This type of salt forma-
tion occurs only in those compounds s^hich
are denvatives of cither ammoma or primary
amines Those compounds which arc denva-
uves of secondary ammes have no remauung
hydrogen on the nitrogen, so salt formation
IS impossible
SulfAibiszole Sodium Sul/uhiuols
(waier intoiuble) (watcr-wbble)
Soluhdily. The sulfonamides which are
weak acids are msoluble m water but solu-
ble m dilute alkali Due to the basic ammo
group, the sulfonamides are also soluble m
solutmos of mmeral aads
locompaUbilily. Most of the mcompati-
bilitics of the sulfonamides are of on ocid-
basc nature resultmg from attempts to dis-
• ? ■ EphcdrmeHydrochlonde
(wttcr-toluble)
Sodium SuITuluuoIe
(Ka(er-«olubIe)
Suir«ihii/ote
(vkicf-tiuolutle)
pense the soluble sodium salu in a slightly
acid medium The sodium salts of the sul-
fonamides m aqueous medium have a pH of
approximately 9 to 10 Aqueous solutions
Aadic Nitrogen Containing Compounds 347
Table 81 Solubilities op Some Sulfonamides and "niEiR Sodium Salts
SoLUBIUrV IN GM per 100 ML OF
Sulfonamide
Water
Alcohol
Ether, etc
Sulf&nilanude
04»
3
s diL alk , dll ac.
Sulfapyndme
003
02
s diLalk., dll ac
Sulfathiazole
006
05
s dll alk., dll ac
Sulfathiazole sodium
40
66
1 eth
Sulfadiazme
0012"
sp s
s dll alk., dll ac
Sulfadiazine sodium
50
si s
1 eth
Sulfamerazine
0016
si s
s dll alk , dll ac , sp s eth ,
aceL, chi
Sulfamerazme sodium
33 3
sLs.
1 eth., chL
Sulfamethoxypyndazme
sJ s
sp s
sp s acet , s dij alk., ac
Sulfaguamdme
01
sp s
s dll ac
Succmylsulfathiazole
00208
sp s
s dll alk
dll ac. = dilute acid
dll aUf- s dilute allfftli
aceL acetone
of the soluble sulfonaicude salts are unstable
m air, resulting m precipitates of the free
sulfonamide due to the absorption of OO^
Color reactions also are observed as the re-
suit of partial oxidation of the drug with the
formation of complex, highly colo^ oxida-
tive products Oxidative Ganges m the sola
tioos can be controlled by the addiaon of
sodium sulfite (0 75 to 2 0 % ) and glycenn
(1%) The sodium salts are too alhahoe
for oral administration and may cause gas-
trointestinal disturbances Some substances
which cause the precipitation of the free sul-
fonamide are mineral acid salts of the sym-
pathomimetic amines (ephedrme HO, d»-
oxyephednne HCJ, Parednne HBr, elc ),
mmera] acid salts of the local anesthetics
(procame HO, tctracame HO, etc ) and
many other substances which yield aad solu-
tions If the substance (HO salts, etc ) caus-
mg the precipitation of the free sulfonamide
IS m low concentration so that it remains
soluble in water in the free form, the sulfona-
mide may be buffered at a stable pH and the
precipitation prevented However, some pre-
cipitation reactions of this nature occasW-
ally are intended by the physician — eg,
nasal solutions containing 5 per cent sodium
sulfathiazole and 2 per cent epbednne hy-
drochloride, etc
Many commercial preparations for mtra-
nasal therapy contammg sodium sulfathiazole
(2 5%), d,l-desoxj ephedrme hydrochlonde
(0 125%), anhydrous sodium su^te (2 0%)
and gljcerm (10%) are dear, stable solu-
tions According to Hamilton ex aJ, the
water-soluble salts can be formed between
the sympathomuneUc amines and the sul-
fonamides These salts were prepared by first
heatmg the aqueous solution given above
unUl all the ingredients dissolved and then
adjustingtoapHof 8 7 witb06 A^HQ
8^0^— CH
Sodium
Sul/atbu2oIe
Desoxyephednae
Hydi^Monde
BARBnVMTES
The barbiturates are another example of
nitrogen-containing compounds with suffi-
aent substitution of acidic groups for the
hydrogens of the nitrogen to cause the re-
mainmg hydrogen to become acidic m
nature
W^CM-CH, C— HH
A
CH,-CH C — NH
Wf O
Aluraie (5-allyi 5 soptopyl
barbituric sod)
348 Ineompahbiniies of Organic Compounds
CX,-eH-Wg-0<, C — KH
V c-o
CH,-CH, C KH
0
Amobubiul (Amytal. 5 eoamyl
9<tliylbirbuurK acul)
0
Wc-W, t—M
X \~
CHj-CH, M
Darboal (S-<liethylbarbaurK
tciJ)
?*»?
CM.— CH,-CM--C C-
e
CHj-CH,'’ 'e-
I .
•KK
Oeivnal (Sodmo 5-<tjiy| $.
(l-methyl i>butcnyl) barbt-
luniel
CM,~CM— CM- C— NM
X
CH,-»CM— CM, e— MH
* • •
Pul (SJ-duUylbarbitmlc
ac«l)
CM,
* ^ * ■ *> / ■ .
A f" "
CM, -CM, C— NM
Orul Solium (SoOium i-n-
hexyl 5<thylbubauraie)
C«-CM,-CM-CH C — M
CM,— CM e K»
rcfttobubaU Soduua (Vctnbuul.
SotlJum-S'Cthy) 5>(1 mnbyl butyl)
batbouraU}
I * II
CH.-CH— CH,-CH C — N
* » * \/ n , +
C C-S No
/ \ I
CM,—CH, C— NH
* * n
0
Tluopcstal Solium (PetuoUul
Sodium, Sodium S<th>! S
(I neihylbutyi) thiobarbauratel
0
Phaaodom (S-cyelohexaiyt
5-<thyl batbiturio acid)
0
Phenobaibaal (S phenyl S-eihyl
barbituric aetJ)
-CH-CHj
-NH
I
C-O
r
Saadcplal (S uobutyl 5 allyl
barbituric acid)
Wi, U
I * I!
CH^CH,-CH,-CH C N
• * • \ / a _ +
C c-o No
/ \ I
CH,— CH-CH, C NH
0
Sc roo al Sodium (sodium 9>
allyl 5 (l-<ncthyU>utyl) bar*
bit urate]
As shoun m the above structures, all of
the important barbiturates arc derivatives in
which various groups are substituted for the
hydrogens on the number five carbon atom,
lliesc barbiturates, which are derived from
Aadic Nitrogen Containing Compounds 349
maloQic acid and urea, are weak acids As
m the case of the irmdes, two acidic carbonyl
groups must be substituted for the hydrogens
of the mtrogen m order for the remaining
hydrogen to become acidic Here the effect
of the individual carbonyl groups is the same
are soluble in alcohol and insoluble m water,
but their sodium salts are readily soluble in
both solvents
Incompatibihly. The major mcompatibih-
ties of the barbiturate drugs are once agam
B. c— . n:h
<^0
as m the acid amides (see p 331) The
tendency for a pair of electrons to shift from
the double bond to form a stable octet on the
oxygen creates an electron deficiency on the
carbon atom In an attempt to satisfy this
deficiency, the carbon atom tends to with*
draw electrons from the nitrogen The un-
shared electron pair of the mtrogen thus
shifts so as to mcrease the covalency between
the nitrogen and the carbon The electron
pair bondmg the hydrogen to the mtrogen,
consequently, is held more firmly to the nitro-
gen, and the hydrogen m turn is held loosely
The combined effect of the two carbonyl
groups makes the hydrogen so loosely held
that the proton is removed easily in basic
solution This migrates to the oxygen of the
carbon atom m number two position to yield
the enol form which then reacts with the
alkah to yield the water-soluble ionized so-
dium salt The reaction may be illustrated as
follows (see bottom of page)
From the structure it can be observed that
only the monosodium salt is possible with
this class of compounds
Solubihfy. The barbituric acid derivatives
Q
ft C“
0 0—0 No + HCK
Sodium Soil ot a Substituted Barbituric Acid
(water soluble)
R C NH
\/ I
C — 0 + Nod
J \ J
fr C NH
Substituted Barbituric Acid
(water insoluble)
those of acid-base reactions Aqueous solu-
tions of the sodium salts of the barbiturates
are alkalme m reaction, and, when aadified,
the insoluble barbituric acid derivative is
precipitated This type reaction takes place
whenever an attempt is made to dispense the
soluble barbiturates m an aqueous medium
cootaming alkaloidal salts, acid syrups, acid
elixirs, salts of many of the vitamins of the
B-complex and other substances havmg an
acid reaction Aqueous solutions of soluble
barbiturates and thiamme hydrochloride, for
example, result m the precipitation of the
r' c — n:h
\/ iHi .
I
-n:h
V
/\
-n:h
11 .
1
-n:h
0
0
II
C-OH
1
'NH
0
I >■
R C N
n t— I
C C-0 |h 1+ NoiOH] — ►
R* C NH
n
\/
A.
0
350 Incompatibilitie* of Organic Compounds
Table 82 Solubilities of Some Barbiturates and Their Sodium Salts
Darbituratb
SoLUDiLmr IN Cm
PER 100 ML OF
Water
Alcohol
Ether, etc.
Aluralc
si s
s
s dll oik
Amobarbital
V st s.
s
s dll all
Barbital. U5 P
0692*
66
2.8S cih , s dll olL.
Barbital sodium
20
s
1 cih
Dclvinol
s
s
1 cth
Dial
V sLs.
s
s diLolk
Ortol sodium
V s
s
1 eih.
Pcnlobarbitol sodium
V s
i cth
Phanodom
V sLs.
s
s dd alL
Phenobarbital
01
10
6 6 eth , s. dll alk , 2.5 chi
Phenobarbital sodium
V s
s
1 cth, chi
Soodoptol
V sL s
$
i dd alk
Seconal sodium
V s
Thiopental sodium
V s
s
1 cth
free baibtiunitc and a dcstrucuoa of the
thiammc acuvuy due to the alLabaity of the
soluble barbiturates la all of the above pre*
etpilaiion reactions, alcohol may be added
(0 solubilize the liberated barbiturate, or the
free barbiturate may be substituted for the
soluble barbiturate and again solubdized by
the addition of alcohol In the ease of the
soluble barbituratC'thiaouac h}drocbloridc
incompatibQity, the free barbiturate and the
alcohol ali\a)s should be used to prevent the
destruction of the thiamine by the alkalinity
of the soluble barbiturate
The soluble batbilutalcs are also incom-
patible t^ath ammonium salts ^ The fol-
lowing reaction takes place between these
substances
V
II - ♦
C-O Ho* + HH.Br-
I
\/
A
C"0 + NaBf4NH,
-NH
Aqueous solutions of the soluble barbitu-
rates hydrolyze to form the RS R* acetyl
urea and other therapeutically tnaetive sub-
stances For example, aqueous solutions of
phenobatbital sodium h)drolyzc to form
phcnyletbylacctylurca The rate of decom-
position IS mflucoced markedly by the tem-
perature and the pH of the solution A 10
per cent solution of phenobarbital sodium at
39* C showed 22 per cent decomposition
m 1 month Soluble barbiturates arc pre-
cipitated from aqueous solutions at pH’s
below 8 8**
HvDAvroiv Compounds
The bydantom compounds arc similar in
structure and reactivity to the barbiturates,
and the mechanism whereby they form solu-
ble sodium salts is also the same as for the
barbiturates
Diphea)lhyiiAmotn Sodium (Dtlatuin,
Sotublo PlicoyioiA, todlum 5,3
dipbenilbyilxatoifl)
Dyes 351
phenylethylbydantom)
FhethenyUle Sodium (Tbi^toia
Sodium, Sodium 5 phenyl 5
2 tbieoyl) bydantoicute)
Dipheoylhydantom sodium is soluble m
water and alcohol It has the same tocom*
patibilities as the soluble barbiturates and is
precipitated from aqueous solution as the free
diphenylhydantoin by acids and acid salts
Unless buffered to a pH of approximately
117, Its aqueous solutions undergo hy>
drolysis, and precipitation of the free di-
phenylhydantoin occurs Phenantom and
phethenylate are chemically sunilar to di-
phenylhydantom
DYES
The synthetic orgamc dyes or so-called
“coal tar dyes ’ are used m mdustry for the
purpose of imparting colors to such sub-
stances as cloth, leather, paper, cellophane,
wood, etc., and as coloring agents for phar-
maceutical preparations V^en used in phar-
maceutical preparations, only certified colors
nhich meet the specifications set forth m the
Food, Drug and Cosmetic act may be used.
Many d)es are also valuable therapeutic
agents which are employed m medicme and
surgery because of their antisepuc, germi-
adal and wound healmg properties
Incompatlbihues mrolvmg dyes are usu-
ally the result of chemical reactions leadiog
to the loss of color or change m color In
order to understand the nature of these re-
actions, a certam amount of background m
the theory of dyes is essential
Theory of Color. The cause of color is
atUibuted to the presence of cer tain chro-
mophore groups within the color producing
molecule These chromophores mclude the
— N=N— (azo), =C=C(thio), -N=0
0 “
(mtroso) , — N=:N— (azo:w) , — N
A
o- o
(nitro), — CH=N — (azomethme), =C=0
(carbonyl) and =C=C=(ethenyl) groups
Other subsutuent groups called auxochromes,
which cause a deepening of the color, may
be present m the molecule The auxochromes
mclude the -NRa, the -NHR and the
groups
Although all organic molecules are capa-
ble of absorbmg hgbt to some degree, most
of them absorb m the ultraviolet* region and
af^ear colorless In other words, they trans-
mit or reflect those rays falling m the visualf
region of the spectrum. According to mod-
em concepts, the theory of hght absorption
IS concerned with the vibrations of the elec-
trons m the molecule m response to the stim-
ulation by hght wates of a ce’lam specific
oscdlauon frequency Where the electrons
are firmly bound m the molecule (e g , as
they are m a saturated hydrocarbon), their
vibration rate is extremely high and they
respond to and absorb hght only of short
wave length and high frequency, which falk
m the far ultraviolet region However, such
is not always the case when the molecule
contams unsaturated groups The valence
electrons of these unsaturated groups are
held more loosely, or we may say that ±ey
are more mobile and arc capable of bemg
set in vibration by li gh t or longer wave
lengths The absorption of hght then may be
m the visible region of the spectrum. In sup-
port of this theory, a simply constructed un-
• Below 4 000 Angsuem umts.
t Visual spectrum includes those wave lengths
between 4 000 and 8 000 Angstrom amts (1 A =
IO-» mm. or lO-io m. or 0 000,000 0001 meter)
352 Incompalibil ties of Organic Compounds
saturated compound usually absorbs light
only in a single limited region of the spec-
trum and, therefore, has an absorption band
of maximum mtensity at a specific w-asc
length As the unsatumtion and the com-
plexity of the molecule increase, scscral ab-
sorbing centers may be created, givmg nsc
to a osmplex absorpuon spectrum composed
of several bands, a senes of peaks or an ex-
tremely broad absorption band The light of
the visual spectrum which is not absorbed
by the compound is transmitted or reflected,
and the compound assumes the color of the
unabsoibcd light Thus, if a compound ab-
sorbs all light of the visible spectrum except
that viewed by the c)c as red, u will appear
to be that color The vanous chromopnorc
groups apparently differ m their activity,
thus, It IS observed that only one azo. thio,
azoxy or mtro group as a substituent on a
benzene nng u sufficient to yield a colored
compound Such is not the case with the re-
maining chromophonc groups listed on page
351 However, as a general rule, more than
one chromophore group is required to >ield
a colored compound, and even in the above
cose the unsaturated benzene nog contnbutes
to the color of the compound
The auxochromes, while incapable in them-
sclv es of ) lelding colored compounds, possess
the ability to augment the function of the
chromophore group and cause an intensifica-
tion of the color According to Bury,** “the
function of the auxochromc is to introduce
the possibility of resonance” in the molecule
In tne resonance structures, more mobility
IS conferred on the valence electrons of the
chromophore groups, which results m on in-
creased light absorption in the longer vvave
lengths In support of the resonance theory.
Bury utilizccl the tnpheQ)lmelh3ne dve,
Deboer’s violet, which shows resonance cue
to the possible existence of two equivalent
structures In order to show the importance
of resonance m the production of color, fuch-
sommme lliN=Ctni=C(Cel 1 s) 2 ] is cited’*
as an example of a compound conlainmg the
same chromophore group (quinoid s^’stem)
but lacking the p-amtno group and devoid
of color, since it is mcapable of resonance
Other structures capable of resonance m-
elude the diphcnymcthane, ammo and
h>droxyazobciizcnc, indammc, mdophcnol,
auraminc, aendme, pyroninc, azine, oxazme
andthiazine J)cs ** The chromophonc groups
are unsaturated and arc usually electron ac-
ceptors The auxochromes arc electron
donors The carboxyl, sulfonic acid groups
and halogens have little effect cither as auxo-
chromes or chromophores
In the d>emg mdustry, the term auxo-
chrome has taken on another meaomg from
that onginally intended In this respect, auxo-
chromes arc rtferred to as groups m the
molecule which confer on the compound the
ability to d)c a substance and yield a fast
color, that is. they * faciJiiatc the attachment
of the d)c to the fabnc”** Many colored
compounds not containing auxochromes are
mcapable of acting as d)cs When considered
from this standpoint, the auxochromes ful-
filling this function may be either acid or
basic m nature These auxochromes mclude
the basic —NRj, — NHR and — NHj and
the atadic —SOiH, — COOH and —OH
groups The basic auxochromes are capable
of causmg an mtcnsification or deepenmg of
color, the acidic auxochromes do not possess
this property D^cs containmg these groups
may be classified as acidic and basic dyes,
those ioTming salts with bases being acidic
dyes and those formmg salts with acids bemg
basic d)cs The sulfonic acid denvauves are
also prepared as a means of mcrcasmg the
water-solubility of the d)'c Certam groups
when subsUluted m the auxochrome also
cause a color change When alkyl and arjl
groups are substituted m the auxochrome, a
deeper color is observed These color-deep-
emng groups are called bathochromes If an
a^l (c g , acetyl) group is substituted m the
auxochromc, the color becomes lighter and
the substituent group is termed a h^pso-
chrome.
Inasmuch as we are conccrocd at this pomt
Dyes 353
only with the chemical and the physical prop-
erties of these dyes, no attempt has been
made to distmguish between those possessmg
therapeutic properties and those used purely
as colormg agents
Most of the dyes used m pharmacy,
whether for their therapeutic or coloring
properties, are salts of acid or basic dyes
The dye ion exhibits greater resonance than
the parent molecule The auxochromes are
capable of forming lonizable salts Any sub-
stance causing a decrease m the ionization
will reduce the mtensity of the color This is
the basis for many mcompatibihties
Classification of Dyes
I. AcndineDjcs
1 Acriflavine (Acnflavme base, a mix-
ture of 3, 6-diammo-lO methyl acridi
mum chlonde and 3,6-diammo acn-
dme)
NH — CH — CH,— N
U. AzoDjes
1 Scarlet Red (Scarlet Red Medicmal,
Biebnch Scarlet Red, <>-tolyl azo-o-
tolyl azo-j3 naphthol)
2 Scarlet Red Sulfonate (Biebnch Scar-
let, water-soluble, the disodium salt
of azobenzenedisulfomc acid azo J3-
naphthol)
CHj cr
2 Acriflavine Hydrochloride (a ma-
ture of the hydrochlorides of 3,6-
diammo 10-methyl acridmium chlo-
nde and 3,6-diamiQo aendme)
3 Proflavine Dihydrochlande (3,6-di-
amino acndine dihydrochloride)
4 Proflavine Sulfate (3,6-diammo acri-
dme sulfate)
-H,sq,
5. Quinacnne Hydrochloride (Mepa-
enne Hydrochlonde, Atabrmc, the
dihydrochlonde of 3-chloro-9-(4-di-
ethylammo-l -methjlbutylammo)-?-
methoxy aendme)
OH
3 Pyridium (Mallophene, phenylazo-
2,6-diammopyridine monohydrochlo-
nde)
4 Serenium (2,4-diainmo-4-ethoxy
azo-benzene hydrochlonde)
354 Incofnpalib Tliet of Orgon c Compounds
5 Congo Red (sodium diphcnjl-diazo-
bis a-Rapbth)Iamine 4^uironate)
6 FD AC Red No I (Poncoau 3R,
the sodium salt of pscudocumylazo*
p napbthol 3,6k1isuuoiuc aad)
7 PDAC Red No 2 (Amaranth, the
sodium salt of 4 sulfo^apbthyiazo*
p naphihol*3,6-disulfooic acid)
8 FJ) AC Red {so 4 (PoQCcau SX»
thcsod]umsaltof5 sulfo-m xylylazo-
o-oaphtbol^^sulfonic acid)
9 FD AC Red No 32 (OU red XO,
m :^l)lazo-/7 napbthol)
10 FJ) AC Orange No I (Orange I,
the sodium salt of p sulfopbcoylazo*
o-napbthol)
o
11 FJi AC Orange No 2 (Orange SS,
o-tolylazo*/7 napbthol)
IZ FDAC Yellow No 3 (Yellow AB,
phenylazo-p naphthylamme)
tn*
O
13 FJ)<tC No (Yellow OB, o-tolyl-
azo*/l naphthylamme)
CM, NM,
-6
14 FDAC Yellow No 5 (Tartrazmc,
the sodium salt of 4-p-sulfopbenyl'
azo-l-p-5ul/ophcnyl-5 hydroxy Ipyra-
rolcO*carboxybc acid)
15 FJ3 AC Yellow No 6 (Sunset Yel-
low FCr, the sodium salt of p-sulfo-
pbenylazo-/! napbthol 6 monosul-
fonate)
Dyes 355
OH
HI# PJilIiaJeiii Djcs
A. Fluorescein (Pyronine) Dyes
I. Fluorescein Sodium (Soluble Fluo-
rescein, Resorcmolphthalein So-
dium; the disodmm salt of fluores-
cem)
2. Soluble Eosin (the disodium salt of
tetrabromoSuorescem)
0
6r Br
3 Merbromin (Mercurochrome; the
disodmm salt of 2,7-dibromo-4'
hydro symercunfluorcscem)
0
HgOH
4, FD&C.RedNo 3 (Eiythrosia;tbe
disodmm salt of tetrmodofiuores-
cem)
B. pHENOLPHiHALEiN Derivatives
1. Phenolphthalein
0
OH OH
2 PhenoUeirachlorophthalem
0
Oh
3 lodophthalein Sodium (tetraiodo-
phenolphthalem sodium, lodeikon)
C Phenolsulfonphthalein Deriva-
tives
1 Phenolsulfonphthalein (Phenol
Red)
356 Incompotibilihet of Organic Compounds
2. Drompheml Blue (tctrabromophe-
nobuUonpbthalein)
IV. TblozintiDjCS
1 T/i:onuie (Laulh’s violcl)
cf
2. Phcnoikazine (Thiodiphcnylaminc)
2. MethylrosaniUiu Chtonde (GcnUan
violet, crystal violet, mctb)l violet,
hcxamcthylparaosaniliae chloride)
3 Malachiie Green (tctramclh)Wi-f>-
aminoinphcn)! catbinol chloride)
3 Methylene Blue (Mclh)’ith>oainc
Chloride, tctramcth)lthiomac chlo-
ride)
4 FDiiC Green No 1 (Guinea
Green, tke mottosodiunt salt d
dibcnz)ldicth)ldiaimnotnphcayIcar-
bino! disulfooic acid anhydride)
V. Triphcnjimcthaiie (RusamUne) Pjes
1. Rosanihne Chloride (FuchsiiJ, Ma-
genu)
5 FDdC. Green No 2 (Dgbt Green
SF Yellowish, the dtsodium salt o(
dibcnz)ldicth)ldiatmnotnpbeo)]car*
bmol uuuUonic acid anh) dndc)
Dyes 357
6 F D &.C Green No 3 (Fast Green
FCF, the disodium salt of diben 2 yl-
diethyldiammohydroxytnphenylcar-
bmol tnsulfomc acid anhydnde)
7 FD&C Blue No I (Brilliant Blue
FCF, the disodmm salt of dibeo^l-
dietbyldiammotnpbeaylcarbiool tri*
sulfomc acid anhydride)
VI. NitroDycs
1 FD&C Yellow No I (Naphthol
Yellow S, the sodium salt of 2 4-
duutro-o-naphlhol 7 sulfonic acid)
N0|
2 FD&C Yellow No 2 (Yellow AB,
the potassium salt of 2,4 dimtro-o-
naphthol-7-sulfomc acid)
o-K*
NO,
Vn. IndigoidDyes
I Sodium Indtgolmdisulfonaie USP
(FD&C Blue No 2, Indigo Car-
mme, the sodium salt of the di-
sulfomc acid of mdigotm)
Incompatibility
The mcompatibihties of the vanous dyes
may give nse to different problems, depend-
ing on their particular use Relative to this
point m the case of the medicinal dyes, we
are concerned mainly with those reactions
which result m a decreased therapeutic
efficacy, whereas with the coloring agents we
are concerned with those reactions m which
a change or destruction of the intended color
IS noted However, the causes of these m-
compatibilitjes may be similar in nature For
example, the precipitation of a medicinal dye
from a solution decreases the therapeutic
value of the solution (antiseptic, germicidal,
cell proliferation activities, etc ) and, when
a coloring agent is mvolved, causes a dimmu-
tion of the mtended color Since the undesir-
able reactions are not entirely limited to the
HgOH
Meibromia
(water-soluble)
HgOH
(water cnsoluble)
253 lnconipolibil>>i«t of Orgonic Compoundt
Tadle S3 SolubiutiesopSomeof tiie More Important
Dyes Used in Piiarmacv
Solubility in Gm for 100 ml op
Dye
Water
Alcohol
Ether, etc.
Acnilasine
33J
si s.
n. 1 cth , chl , f oils
Acnilavine H>drochlonde
33J
s.
n i elb , chl , f oils
Amaranth. F DAC Red No 2
s
sp. u
s giy , i cth.
Bismarck Drown
s
%
s. CtL
Dromphcnol Blue
sLs.
s.
si s cth , di] allc
Congo Red
to
B
t eih.
PDJ.C Blue No 1. Bnlliant Blue FCP
t
S
s. gly , 1 cth
FD.^C Green No t, Guinea Green
P D iC Green No 2, Light Green SF
s
AS
s. gly , i cth
Yellow ish
S
s
s.gly .1 cth.
F O Green No 3, Fast Green FCF
si s
s gly , i elb
FD&C Orange No I, Orange No 1
s.
03
s gly . 1 cth.
F D iC Orange No 2 , Orange SS
I
s.
s oils, si s gly
FDJ,C Red No 1, Ponceau 3R
s
si s.
s gly , i etb
FD&C Red No 3. Eryihrosin
1
s
s gly 1 eth
FDiC Red No 4, Ponceau SX
si S
s gly . 1 cth
F D.AC Red No 32, Od Red XO
t.
s] s.
si s gly . s oils
FDiC Yellow No 1. Naphthol Yellow S
s
si s.
s gly . 1 eth
FDiC Yellow No 2. Yellow AB
s
si s.
FDiC Yellow No 3. Yellow AB
1
si u
sp s gly , 1 oils
F D iC Yellow No 4. Yellow OD
1
s
si s.cly,s oils
F DilC Yellow No 5, Tartnmoe
s
si 1
F D.iC Yellow No 6. Sunset Yellow FCF
s.
si t
>Sy
1 euL
riuoresccin Sodium
s.
lodophthalem Sodium
143
si s
1 cth
Malachite Green
s
t
s amyl a]
Merbromm
s
i
i acet , chl , eth
Mcth)lcne Blue
40
IJ
$ chl
Meth)lrosaniline Chloride
30
too
6 6 gly . s chl , 1 cth
PhcnolphUulcm
0018»
66
lOcth.s dll tilk
PhenoIsuUonphtholcm
0 076
0 285
L chl , cth
Phcnohcirachlorophthalcin
1
s.
s cth acet dil alk.
Phcnothiazine
1
IJ3
ZOOacel .5 0chl
Proflavine Dih}drochIonde
too
s
si $ eth , chl . Iiq pet
&JJ4
tls.
a tct}!,chl,}!q pet
P)ndium
1 0
s.
1 acet bz.. chl , eth , oils
Quinaenne HjdroehlonJe
30
s
n 1 cth
Kosanihnc
U s
s
1 cth
Scarlet Red
1
si s.
Scarlet Red Sulfonate
Serenium
Sodium Indigotindisulfonalc, UJJ* F DJLC
s.
s
si t
si s cth , 1 bz., chl , f oils
Blue No 2
•
s. gly , 1 cth.
Soluble Losin
s
L eth
Thiomne
1
sLs.
s. cth.
specific use of the compounds, no separa-
tloa IS made bclsvccn ihe mediaDo) d}es aod
the coloring agents in the following discus*
Sion of their incompatibilities.
Although htUe has been ssnttcn concern*
mg the incompaubilitics of the dyes, a study
of a few of their reactions will ser>e to
acquaint the student with some of the prob*
Dyes 359
Table 84 Resistance of the F D &C Certified Dyes to Various Conditions
Influencing Their Color Stability in Pharmaceutical Preparations
FD&C Certified Dyes
Reducinq Oxidizing
Alkali Agents Agents
moderate moderate good
(VaterSoiubte Dyes
FJD&C Blue No I, Brilliant Blue good
F D &C Blue No 2, Indigo
Cannine poor
FD&.CGreenNo l,GuineaGreen poor
F D^C. Green No 2, Light Green
SF Yellowish poor
F D &C Green No 3, Fast Green
FCF good
Orange No I, Orange I moderate
FD&C Red No 1, Ponceau 3R good
F D &C Red No 2, Amaranth moderate
PD&C Red No 3, Erythrosme fair
F D^C Red No 4, Ponceau SX fair
FD&C Yellow No 1. Naphthol
Yellow moderate
P D &C. Yellow No 2, Naphthol
Yellow (K salt) moderate
P D.&C Yellow No 5, Tarirazme good
PD &C. Yellow No 6, Sunset
Yellow FCF good
OilSotubte Dyes
F D &C Orange No 2, Orange SS fair
FD &C Red No 32, Oil Red XO fair
FD&C Yellow No 3, Yellow AB poor
P D &C Yellow No 4, Yellow OB poor.
good
moderate
moderate
poor
good
poor
good
poor
good
poor
good
poor
good
poor
good
poor
moderate
moderate
poor
fair
good
good
poor
fair
good
good
poor
fair
poor
good
moderate
fair
poor
good
moderate
fair
good
good
fair
fair
gjod
good
fair
fair
good
good
poor
fair
good
good
poor
fair
poor
poor
poor
fair
poor
poor
poor
poor
lems which may anse m the dispeosmg of
them As a general rule, it may be stated that
basic dyes are incompatible with those or-
ganic substances which yield a large ncgaDve
ion on ionization. Eztendmg this point, we
find that soaps, tannms, acidic dyes, etc , may
yield precipitates with the basic dyes, al-
though m many cases it is a very slow re-
action. Conversely, the acidic dyes often
yield precipitates with those substances
which give nse to a large positive ion on
ionization
The sodium and the mmeral acid salts of
acid and basic d^es arc prepared in order to
facilitate the solution of the compound m
Water \Vhen these salts are placed in an
aijueous medium v.hich destroys the salt, m
compatibilities often result. For example,
Merbromm is precipitated readily m an
aqueous acid medium Mmeral acid salts of
such substances as local anesthetics, sym-
pathomimetic ammes, etc , cause similar re-
actions However, acidic dyes which arc the
sodium salts of sulfomc acid are not aSected
appreciably by acids or mmeral acid salts of
orgamc compounds (see Table 84) This be-
havior of the sodium salts of these acidic
sulfomc acid dyes toward acid is explamable
on the basts that sulfomc acids are strong
acids so susceptible to ionization that they
are capable of canymg large molecules mto
solution in water
Acndinc Dyes. The acndine dyes mclude
acriflavme, acnflavme hydrochloride, pro-
flavme dihydrochlonde and proilavme sul-
fate Acnflavme is mcompatiblc with solu-
tions m ntaintn a cblorwe, pheool, silver
mtratc, mercuric chlonde and alkalies Solu-
tions contaming sodium chlonde yield a
preapitate on standmg” Hus preapitate
may be explamed on the basis of the solu-
bility product
360 IncOfflpoIibiGtiet of Orgonlc Compounds
tVoiUvme Di^yJfocMorh]o
Ac^ucous solutions of proHaMnc dih}dio*
chlonJe precipitate the )cllow prol^vioc
base on tlic addition of sodium h)droxide
Sd’.ec nitrate T5 produces a precipitate of
Sliver chloride with an aqueous solution of
proflav me dih)droch]oridc
jVzo Djcs. On referring to the reactions
of the azo compounds, it is observed that
ozobcnzcnc is reduced rudily m aikalmc
solution to h^drazobcnzcnc and ultimately to
aniline by acid reduction Comparable tcduc-
Protlaiino Ba.e
On referrmg to Table 84, it will be observed
that the FD&.C dyes (red 1, 2 and 4,
orange 1 and 2, and yellow 3, 4 and 6)
possess little resistance to color changes
brought about by the presence of reducing
agents Scarlet red, for example, is con-
verted by reduction to the Icuco (colorless)
compound
Phtbalcm Dyes. The phthalcin dyes may
be divided into three groups ( 1 ) the fluores-
cein (pyrOQinc) group, (2) tlie phenol-
raCueilen
elkolin*
I()iJruobeiucii«
Aiulioe
uon reactions also may take place with the
azo dyes m the presence of reducing agents
Lctwolorm
phtbalcm group and (3) the phcnolsulfon-
phthalcin group They may also be classified
as triphcnylmcthane dyes The compounds
of the first nvo groups are derivatives of
phthahe anhydride and phenols, the mem-
bers of the latter group arc derivatives of
suUobcnzoic anhydndc They arc all used
m pharmacy as dyes and mdicaiors In gen-
eral. these compounds arc water-insoluble
but become water-soluble and highly colored
on the formation of tlicir sodium salts
The leacuons of the fluorcseem com-
pounds may be illustrated with fluorescein
The color of fluorescein is due to resonance
which allows for die presence of the qumoid
chromophorc group m the molecule Thcrc-
Ftuoraceia— Ke$ocuAC« Fonu
Dyes 361
fore, the above resonance structures are pos-
sible m fluorescein In alkaline solution, the
following reaction takes place
Fluoresoeia Sodium
(water-soluble)
out of a molecule of water which results m
the formation of the chromophore qumoid
group If more alkali is added, the tnso-
dium salt is formed and the solution again
becomes colorless The loss of color is
brou^t about by the destruction of the
quinoid structure The addition of acid re-
verses these reactions and the leuco form is
agam obtained
Tnphenjlmcthane Djes. The tnphenyl
methane dyes owe their color to the presence
of the chromophore qumoid group m the
molecule Because these dyes are reduced
readily to the leuco form, mcompalibihties
may anse when they are dispensed with re-
ducing agents The followmg reaction with
pararosanilme, on page 362, illustrates this
phenomenon
In the presence of alkah, the hydrochlonde
salts of the basic tnphenylmethane dyes are
DisodiumSalt TnsodiumSalt
(waler-soI(d>le) (colorlc&s)
(nd color)
Phenolphthalein may be used to illustrate
the formation of a salt and the production of
color An analogous reaction tal«s place with
the phenolsulfonphthalem derivatives
On the addition of alkali to a solution con-
tainmg phenolphthalem (or similar com-
pound), the water soluble ionized disodium
salt is formed and the soluUon turns red
The production of color is due to the sphtting
converted to the colorless carbmol base The
colorless carbmol base may then be reduced
to the leuco base * This type of mcom-
patibihty is shoivo readily Viith malachite
green and methylrosanilme chloride
In addition to bemg incompatible with
reduemg agents and alkahes, melhylrosani-
Ime chlonde (gentian violet, methyl violet,
crystal violet) is mcompatible with acids
362 IncoRipot bil lies of Orgonic Compounds
NH,
Leu£os>anrosifiilirhe
(color leu)
The addiUoQ of aad causes the color to change
from violet to green to )eIIow The citplona
tion of this color change lies m the faa that
the acid prevents the remammg basic groups
from contributing to the resonance which u
possible in the ongmal structure.^* Mcth}l*
rosaniline chlonde (gentian violet, ci}stal
violet) fields a precipitate with tannic acid.
Tbiozinc Djes. Tlic tbiazmc d)cs, which
include ihionine, phenothiazinc and meth)N
cne blue, may resonate between several pos-
sible forms Klcthylcnc blue is, perhaps, the
most important of this group Three of its
possible resonance forms are shown below
Mcih)lcnc blue is reduced readily to the
colorless compound Other incompatibiliucs
include color changes wills acids and alkalies
M<ih>lrManiIineCIilarhl« $rcca color)
(viold color)
Glycosides 363
Malachite Creen
(chlonde)
Acids cause the color to become a lighter
shade of blue, a purple shade is obtained with
alkalies An excess of sodium hydroxide
yields a violet precipitate on standmg These
incompatibilities are shown in the followmg
reactions Other incompatibiliUes of a pre-
cipitation nature are caused by iodides,
mercunc salts, thiocyanates and permanga-
nates
Nttra D^vs. Tbs mtio dyes exhibit <}aly a
fair resistance to the inSuence of reduemg
agents Aromatic mtro compounds are, of
course, oxidizing agents and may be reduced
to the corresponding ammo compound The
mtro dyes are also susceptible to reduction
and, thus, m Table 84 it is observed that the
mtro dyes F D &C No 1 (Naphthol Yellow
S) and F D &C Yellow No 2 (Yellow AB)
manifest only a fair amount of resistance to
the color changes brought about by leducmg
agents
Indjgoid Dyes. These dyes may be re-
duced to the leuco (colorless) form The
following reaction with indigo cannme (So-
dium Indigotin Disulfonate, U S P) illus-
trates the change brought about by reduc-
tioa as shown on tbs followiag page
On oxidation, the color of indigo carmine
IS changed from blue to green to light yellow
From these reactions, it is observed that
both oxidizmg and reduemg agents may be
potential causative agents for incompatibil-
ities for these dyes However, m practical
use it IS found that indigo cannme has a
moderate resistance to reduemg agents but
poor resistance to the activity of oxidizmg
agents (see Table 84) Indigo cannme is
preapitated by sodium chlonde from aque-
ous solutions, and sodium hydroxide causes
the color to change from blue to yellow
GLYCOSIDES
The term glycoside designates that class
of compounds which, on hydrolysis, yield a
sugar and a nonsugar component More
364 Incompolibililies of Organic Compounds
CUBuae
No 0^
spccificaily ihc gljcosidcs may be designated
according to the sugar they contain Thus
gl)cosidcs yielding glucose on h)drolysi$ are
termed glucosidcs, those yielding fructose,
fructosidcs, those yielding rhamnose. rham*
nosidcs Houcter, glucose is the most com*
mon sugar component of the glycosides The
nonsugar component is called the aglucon
The aglucon component of the glycoside
molecule tarics widely in its com^sition
from simple alcohols to complex steroid
structures, but the presence of at least one
hydroxyl group ciUicr as an alcohol or a
phenol IS cssenual The glycosides may be
classed as sugar'Cthers but they arc, per*
haps, more correctly termed acetals Like
lire synUtctic acetals the glycosides arc not
hydrolyzed by alkalies but can be hydrolyzed
by acids Some arc hydrolyzed rcaddy by
weak acids at room temperature, whereas
others arc much more resistant and require
drastic treatment m respect to (he time, the
temperature and the concentration of the
acid necessary to bring about hydrolysis
Solubility. In spite of ihcir large molecular
weight, most glycosides arc soluble in water
and alcohol owing to the poly hydroxy sugar
component which associates with water
through hydrogen bonding Howeser, the
phytosicrohns arc quite water*insolub!c The
glycosides arc insoluble in ether b(.cause of
the large number of functional —Oil groups
After hydrolysis, the sugar is soluble in
water, but the a^ucon usually is insoluble
Itieumpalibilily. Some incompatibilities
may develop in prescriptions if acidic sub*
stances capable of hydrolyzing the glycoside
ore present. .Many glycosides arc precipitated
by tannic acid and soluble heavy metal salts
Some of the more important glycosidc-oon*
taming drugs arc digitalis, gentian, gly^T-
rhiza, yalap, squill, strophanlhus and buck*
wheat, which is the mam source of Ruim,
NF
RESINS
The resins arc a class of ill defined plant
substances often desenbed as natural or in*
duced, solid or scmisolid exudates of plants
which arc soluble m alcohol but insoluble in
water They arc believed to be oxidauve
products of the tcrpcncs and, as such, they
vary greatly in their chemical composition
A distinction is often made between the
naiurally occurring resins and die prepared
resins, the latter type is prepared by extract-
ing (he crude drug with alcohol, pouring the
extract into an excess of water, and filtering,
washing and drying the precipitate Gum
resms are natural exudates of plants consist-
ing of mixtures of gum and resin Olcorcsins
are mixtures of volatile oils and resin Bal-
sams arc resinous substances containing
bcnsiic or cinnamic acids or their esters
Although, as stated above, the resins vary
widely in chemical composiLon. most resms
have one point in common m that they con-
tain a large percentage of acidic substances
From this standpoint, no dutmction need be
mode between natural resins, prepared resms,
olcorcsins or balsams in a discussion of their
inoompatibilities in prescriptions Some of
the more important resms, resmous sub-
stances and resin-contaiiung drugs are
uofcUda, ospidium, benzoin, capsicum, co*
Anhbiotics
365
paiba, gamboge, ginger, guaiac, ipomea,
jalap, kamala, mastic, myrrh, Peru balsam,
podophyllum, rosm, storax and Tolu balsam
Incompatibility. Resms are precipitated
from their alcoholic solutions by the addition
of water Smce these substances are acidic m
nature, almost all of the resms are soluble
m solutions of alkali hydroxides due to the
formation of their sodium salts With heavy
metals they form insoluble salts Because
many of resm acids contain phenolic
hydroxyl groups, they give color reactions
with feme chloride and, as a general rule,
are incompatible with oxidizing agents
Such substances as Peru balsam copaiba,
etc , although not soluble m water, can be
dispensed m an aqueous medium by forming
an emulsion In tLs case, castor oi! can be
used to dissolve the resmous substance, and
the emulsion then prepared m the usual man-
ner Castor oil is useful in this respect for
external preparations m that it is composed
of the tngljcende of ncmoleic (12 h)dfoxy-
oleic) acid, the presence of the —OH group
enables it to associate through hydrogen
bonding with the acidic constituents of the
resins to solubilize them
Peru balsam and other resinous substances
m the form of viscous liquids separate from
omtments when the base is composed solely
of a nonpolar substance such as petrolatum
Emulsifying agents such as wool fat, glyceiyl-
monostearate, etc , or castor oil will prevent
this separation
SILVER PROTEIN PREPARATIONS
The different silver protein compounds
vary widely m composition but generally
consist of msoluble compounds such as silver
oxide, metallic silver, stiver halides or some
prolem silver precipitate and denatured pro-
tern®^ The commercially available forms of
silver protem compounds may contain m-
soluble silver compounds in which the silver
IS apparently m actual chemical union with a
protein or its hydrolytic products, or they
may be colloidal metallic silver, silver oxide
or other salts and the denatured protem
According to the N F , * Mild Silver Protein
IS Sliver rendered colloidal by the presence
of, or combination with, protein ” The N F
does not state deffmtely the exact chemical
composition of mild silver protem other than
to list the percentage (19 to 23%) of silver
that the compound must contam, however,
the silver is probably present as the mer-
captide salt.
Incompatibility. As a general rule, it may
be stated that these silver preparations are in-
compatible with the soluble alkaloidal salts
The difficulty here anses from the gradual
formation of the insoluble silver salt of the
acid with the hbcration of the msoluble alka-
loid Husa*® states that silver protem com-
pounds are also mcompatible with tannm,
acids and lodme Here the mcompatibihties
are due to ( 1 ) the formation of the msolu-
ble silver tannate, (2) the fonnation of the
silver salt of the acid and (3) the formation
of the msoluble silver iodide
Mild Silver Protein Preparations
Argyrol is a mild stiver protem compound
coDtammg 20 per cent silver combmed with
protem It forms stable colloidal solutions
havmg an approximate pH of 9, a silver ion
concentration of approximately 10~’ and a
particle diameter of approximately one tenth
to one hundredth that of Staphylococcus
aureus (Staphylococci have a diameter of
07 to 0 9/1.)** Argyrol SS solution con-
tains 10 per cent mild silver protem and is
stabilized with 10 mg per ml of the com
plexmg agent disodium calcium ethylenc-
diamme tetraacetate
NeO'SilvoI contams 18 to 22 per cent of
silver iodide and yields colloidal aqueous
solutions It is stabilized with gelatm Nco-
Silvo! IS miscible with water to the extent
of 25 per cent, it is slowly soluble m glycenn
and msoluble m fixed oils
Silvol IS a mild silver protem preparation
contammg approximately 20 per cent silver
with an alkalme protein It is freely miscible
with water, with which it yields a colloidal
solution with a very low percentage of free
silver ions
ANTIBIOTICS
This group of therapeutic agents, which m
the common pharmaceutical terminology has
become known as the antibiotics, vanes
greatly m chemical composition Because of
the great differences m the chemical nature
366 Incompohbilities of Organic Compounds
of the antibiotics, it is not logical to treat the
subject of their incompatibilities as a class of
compounds Hie mcompatibilitics of each
substance must be considered in an mdi-
vidual manner Actually, the problems en-
countered by the practicmg pharmacist m
the compounding of these antibiotic sub-
stances tend to be reduced by the manner m
which they arc presenbed and used How-
ever, It is essential for the pharmacist to
know the reactions of these substances m
order to understand not only the possible m-
compatibilities which may Im encountered in
compoundmg but also the problems mvotved
in product formulation, storage and the limi-
tations of the various modes of administra-
tion No attempt has been made in the fol-
lowing discussion to provide a complete list
of the microorganisms against which the in-
dividual antibiotics are cilective, smee the
therapeutic use of these agents is not withm
the scope of this chapter
Bacitracin
Bacitracm is a neutral polypeptide ob-
tained from cultures of Bacillus subtilts,
siniin Tracy I It is active against many gram-
positive and certain gram negative organisms
and frequently is active against organisms
which have become resistant to peoiciUm It
can be used by mtramuscular injection
against systemic infections, but its mam use
at the present time is by topical application
against infections of skin, eye, nose and
throaL Bacitracm does not yield detectable
blood Icicls when given by the oral route
Solubility. Bacitracm is soluble m water
and alcohol but insoluble m acetone, ether
and chloroform
Incompatibility. Bacitracm can be pre-
cipitated from aqueous solution by high con-
centrations of soluble morganic salts such as
sodium chloride It also is precipitated and
inactivated by heavy metal ions’ and tannic
acid Salicylic acid likewise causes bacitracin
to be precipitated, but the precipitate main-
tarns antibiotic activi^. Aqueous solutioas
in general arc unstable, however, m neutral
or sightly acidic solution, activity is rctamed
for long penods if the solution is refrigerated
at 0* to 5“ C At 37® C., inactivation occurs
m 2 weeks In alkaline solution (pH 9 and
above), the antibiotic is macuvated rapidly
In the dry form, bacitracm is stable at
temperatures up to 37® C It is also stable
m anhydrous hydrocarbon omtment bases
but rapidly loses its activity m the water-
misciblc bases ^ It is reported that bacitracm
omtments contammg polyethylene glycols
and propylene glycol lose 50 per cent of their
activity withm a week at room temperature “
Chloramphenicol
Chloramphenicol (Chloromycetin, d-
r/ii-eo-l-p-nitrophenyl-Z-dichloroacctamido-
1,3-propanediol) was obtamed ongmally
from cultures ot Sireptomyces venezuelae but
O ljlH-C^CHClj
CH-CH-CHjOH
OK
1 $ now prepared by chemical synthesis It is a
broad-spectrum antibiotic which is c0ective
against certam gram-negative bactena, spiro-
chetes, nckettsia and larger viruses
Solubility. Chloramphenicol is only
slightly soluble m water (025%) but is
soluble m alcohol, acetone, ethyl acetate and
propylene glycol The palimtate ester is veiy
insoluble m water, thus the extremely bitter
taste which characterizes the parent com-
pound IS decreased significantly so that the
ester can be employed satisfactorily m aque-
ous suspensions for oral use
Incompatibility. Chloramphemcol is a
much more stable compound than either pcni-
cdlm ot strcptQtajcmv however^ a is rapidly
macuvated m dilute aqueous alkali At pH
10 8, chloramphenicol is over 87 per cent
macuvated in 24 hours at 25® C It is rela-
Uvciy stable m neutral and aadic soluUons
In the dry form, the antibioUc is very stable
at room temperature
Cycloserlne
Cycloscnno (Seromycm, D-4-ainmo-3-
isoxazobdone) is an anUbioUc substance pro-
duced by Sireptomyces orchldaceu^' or
Sireptomyces garyphalus “ The compound is
effccUve against the mjcobactcnum tubercu-
losis organism and is thus employed m the
trcaimeot of severe pulmonary tuberculosis
Cycloserine is soluble in water (10 Cm
Antibiotics 367
0.,,^ c=o
per 100 ml at 25® C ) The compouad is
stable m alkalme but unstable m neutral and
acidic solutions
Erythromycin
Erythromycm (Ilotycm, Erythrocm) is a
broad spectrum antibiotic obtamed from
Streptomyces erythreus It is somewhat sim-
ilar to penicillm m antibacterial acttvi^ and
allegedly does not produce the profound
changes m the mtestmal flora which is often
observed with the use of other broad-
spectrum antibiotics
The antibiotic has the followmg formula,
and, smce it contams basic mtrogen m the
molecule, it is capable of forming salts with
acids
destroyed rapidly in aqueous solution by both
acids and alkalies It is most stable m the
range of pH 6 to 8 and is mactivated very
rapidly at pH 4 and below Therefore, the
free base and the soluble salts are mactivated
m the stomach unless given m the form of
entenc-coated tablets However, the msolu-
ble stearate and the ethylcarbonate esters are
not destroyed by the acid of the stomach and
thus can be admmistered m the form of aque-
ous suspensions as previously stated
Neomycin
Neomycm (Mycifradm) is a basic com-
pound obtamed from cultures of Strepto-
myces Uadiae It manifests antibiotic activity
agamst both gram positive and gram negative
bacteria and is particularly effective against
staphylococci Thus, it is widely us^ by
topicd administration, m both the solution
and the omtment form, for the treatment of
skm mfecuons It is also admmistered orally
as an mtestmal antiseptic
HOfA.
CH.
HC-CIS
KCOH
\ OH
-CH
HC-CH,
I
^COH
CH, CH,
SoIubiUty. The free base is poorly soluble
m water (0 2% ) but is soluble m alcohol,
acetone, ^oioform and ether The hydro-
chloride salt IS soluble m water (4 0%) but
the stearate and the ethylcarbonate esters are
water insoluble Because of their msolubihty,
these esters are not so bitter tastmg as the
free base or the soluble salts and, therefore,
are particularly useful m pediatnc prepara
tions m the form of aqueous suspensions
Incompatibility. Erythromycin, both as
the free base and m the soluble salt form, is
Solubility. Smce Neomycm is a basic com
pound. It forms salts widi acids Neomycm
Sulfate IS soluble m water but insoluble m
most organic solvents
Incompatibility. Neomycm is more stable
m aqueous solution than many of the other
antibiotic agents and is even acuve m alka-
lme solution * Its stability range m solution
IS between pH 1 5 and 12 ^
Novobiocin
Novobiocin Sodium (Cathomycin So-
363 {ncompatibiliiies of Organic Compounds
dium, Albamycm) is the salt of an acidic
substance produced by the organism Strepto-
myccs This antibiotic is effec-
U\c against gram posiute organisms and i$
especially useful against resistant strains of
staphylococci
S^osobiocm as the sodium salt is \ery
soluble m water and is also soluble in alco-
hol, glycerin and propylene glycol The anti-
biotic IS relatively stable under both acidic
and alkaline conditions and thus can be dis-
f lensed m liquid as well as dry solid dosage
orms Novobiocin (Cathomycm Calcium) is
also available as the calcium salt This salt is
soluble m natcr (0 4 Cm per 100 ml ), m
alcohol (3 3 Gm per 100 ml ) and m ether
(022 Cm per 100 ml )
Oleandomycin
Oleandomycin phosphate is an antibiotic
substance obtained from the growth media of
Sueptomyces antibioticus This compound is
effective against gram positive organisms and
is particularly useful against staphylococci,
streptococci and pneumococci
Tins antibiotic contains basic nitrogen’*
in Its compict structure and thus is able to
form water-soluble salts with acids It is m-
cludcd in the macrolidc group of anubtoucs
of which erythromycin is also a member
Olcandomycm phosphate is soluble m
water (45 4 Gm per 100 ml ), in alcohol
(33 3 Gra per 100 ml ) and is slightly solu-
ble in ether
Tnacclylolcandomycin (Cyclaroycin,
TAO), the tnacctyl ester of oleandomycin,
IS only slightly soluble m water and ether but
IS soluble (10 Gm per 100 ml ) m alcohol
Because of Its decreased water solubility it is
more stable in liquid preparations than salts
of the parent compound and is often used lo
in the form of a suspension.
Penicillin
Pcnicdlm is obtained as a growth product
from the molds Peniallium noiaiuni and P.
chrysogenum Thom (Fam AspergiUaceae)
PemciUm G also has been prepared syn-
ihcucally The antibiotic substance obtained
from these molds has been shown to be a
muturc of chemically related substances The
fermentation liquors contam mainly peni-
cillin G, smaller quantities of K and F, and
vanable amounts of the other pcmciUins In
various commercial procedures, the produc-
tion of penicillin G has been increased by the
process of adding certain precursors such as
phcoyiacctamidc and pbenylacetic acid to
the media, whereas the addition of S-aUyl-
mercaptoaccue acid to the fcnncntation broth
yields [woicilJm 0 All of tlie known naturally
occurring pcnicilliDs are derivatives of the
parent p lactone structure shown below and
differ only in the nature of the R radical
ft — C — NM— CH — CH C
I I I'w, ,9
O-C— H W C-OH
Parent Structure of PenicilUn
The following arc some of the more im-
portant pciuciUtns
ftnicillin G It " ^ (Uenzyl)
PauctUiaPft — CHj-CH,—
PcnicUIuikR “ (n llept>l)
PenKilUaO R= CHj^CH-CHj-S-CHj-
Antibiotics 369
Penicillin V - o- 0-CH^-
Penicillin X
R =g (p-Hydro*ybenzyI>
Owing to the manner m which pemciUm
1 $ prescribed and used, few incompatibdities
are encountered in the actual dispensing of
the drug However, there are many important
points concerning its stability which the phar-
macist must know.
Solubibty. The free acid of penicillm is
insoluble in water and decomposes readily
The aikah and the aikahne earth metals aU
form water soluble salts, but those sails de-
rived from heavy metals are only slightly
soluble m water Pemcnim is also soluble m
gjycerm and alcohol, but these solvents cause
It to be uiactivated The salts denved from
vanous amines such as procaine (Procaine
Penicillin G) or N,N'-diben^lethylencdia-
mine (Benzathine PeniciUm G, Bictllio)
have poor water*solubility
Incompatibility* Aqueous solutions of
peniciUm readily decompose with a loss in
potency even when refngerated In solutions
havmg a pH of 5 or less, the free acid of
penic^in is precipitated Solutions having a
pH 8 0 and above cause a rapid deteriora-
tion of the penicillin The incompatibilities of
pemcillut la aqueous saluuoa may thus be
summarized as follows (1) precipitated and
inactivated by acids and heavy metals, (2)
inactivated by alkalies (pH 8 0 and above),
gl}cena and alcohol, and (3) mactivated by
oxidizing agents Since penicillm is pre-
cipitated and mactivated by acids, it is in-
compatible m the acid medium of the stom-
ach In this case, the penicillin is mactivated
before absorption can take place m the small
intestme This may be classed as a thera-
peutic or physiologic incompalibiliiy In
order to facil tate the oral admmistration of
penicillin, buHcnng agents such as aluminum
hydroxide, calcium carbonate, anhydrous so-
dium citrate, etc , may be added to pem^in
tablets or solutions to reduce the hydrogen
ion concentration of the stomach In this way,
the destruction of the penicillin m the stora-
adi IS decreased In the alkaline fluids of the
body such as saliva, enteric juices and bile,
the pH range usually falls between 5 0 and
8 0, and the drug is not destroyed so readily
Even so, following oral adimnislration with
these precautions, roughly only about one
fourth of the ingested penicillm is absorbed,
thus, much larger doses are required with
this route of admmisliation
Because of their water msolubility, Pro-
caine Penicillm G and Benzathine Pemcil-
liQ G are more stable m an aqueous medium
than the potassium salts The aqueous sus-
pensions are used both orally and paren-
teraily and are stated to retain their activity
for long penods of time Therapeutically,
these insoluble forms are of value because,
after parenteral admmistration, they mam-
tain hi^er and more constant pemcillm blood
levels than the more soluble forms
Pemcillm ointments remam active for a
long penod of tune if they are compounded
without first dissolvmg the drug m water but
incorporated m anhydrous omtment bases
However, the area to which the ointment is
to be appbed governs to some extent the type
of omtment bases used When pemcillm oint-
ments are intended for applicaoon to mucous
membranes, the drug, m the dry form, may
be incorporated mlo a base which is capable
of absorbmg water Solution of the penicilhn
then takes place m the aqueous fluids of the
membTancs to which the ointment is applied
Polymyxin
The polymyxins are denved from vanous
strains of the spore-formmg soil bacterium
BaciHus polymyxa (B aerosporus) All the
known members of the polymyxm group
(A, B, C, D and E) are basic polypeptides
and therefore are capable of fomung water-
soluble salts with inorganic acids The poly-
myxins are effective agamst most gram-nega-
tive organisms This anubiotic is used mainly
by topical application but also can be given
orally for infections of the gastro-mtestmal
tract.
Solubility. Polymyxm B sulfate and the
hydrochloride salts are soluble m water but
370 Incompalib Iihes of Organic Compound^
insoluble m most orgamc solvents As the
free bases, the polymyxins are only sbghtly
soluble m Vratcr and arc msolublc m alcohol
Incompalibilily. The polymyxms are in-
compatible m aqueous solution with strong
acids and alkalies Such solutions rapidly lose
their antibiotic activity even at room tem-
perature However, m less acidic and in neu-
tral solutions (pH 2 to 7), the antibiotic is
stated to be thermostable *
Streptomycin
Streptomycm is produced by the actino-
mycctc, Strepiomyces gnseiis and is obtained
as a growth product of this orgamsm.
Chemically, streptomycm is an osgamc
base composed of strcptidme (1,3'diguaiu
dmo-2,4 S 6 tetrahydroxycyclohexane) and a
disacchandclike component streptobiosamme
jomed through a gljcoside Imkagc The
streptobiosamme portion of the molecule is
composed of streptose and N mcihyl-1 glu-
cosamine The structure of streptomycm is
shown below (CsiHjjNtOu)
Due to the presence of the basic mtrogen
m the molecule, streptomycm forms salts
with acids It IS available as the bydrochlo-
nde, the sulfate, the phosphate and the strep-
tomycm calcium chlonde complex known ns
streptomycm tnhydrochloride calcium chlo-
ride [(CjiHssNtO, a SHaijCaOsl Reduction
of the iddehjde group to a primary alcohol
m the streptose portion of the molecule yields
dihydrostrcptomycm
Mlubdit). Streptomycm and its sails are
very soluble m water but insoluble m chloro
form, ether and other nonpolar solvents
locompalibihty. In the dry crystallme
form, It 15 quite stable at room temperature,
but as a precautionary measure against de-
composition It should be stored at tempera-
tures not exccedmg IS” C Aqueous solu-
tions arc stable at room temperature for
1 week, but elevated temperatures cause
rapid deactivation of the streptomycm The
optimum pH for stabihty of streptomycm
m water is 4 5 to 7 0 Dihydrostrcptomycm
IS more stable to alkali than streptomycm
Tetracyclines
Tbe tetracyclmes compose a group of
chemically similar agents bavmg similar
broad spectrum antibiotic activity These
agents are cfifortctracyclme (Aureomycm),
oxyietracyclme (Terramycm) , tetra^clme
(Achromycin, Tetracyn) and dcmethylchlor-
tclracyclme (Dcclomycm) Chlortetra^cline
IS obtamed ^om the organism Streptomyces
mireofaciens, whereas oxjtetracyclme is ob-
tamed from Streptomyces nmosus Tetra-
cycline can be prepared by reductive dc-
chlonnaiion of chlortelracycimc * As is
observed from their structures, these sub-
stances are amphotenc since they contain
both acidic and basic groups m the molecule
Chlortetncrdinfl
0
OH 0 OH 0 'NHj
OxytAracyclme
TetracrcUae
Vitamins 371
Cl OH CHa-N-CHa
Demethylchlortetrocycime
They are thus able to fonn salts with either
acids or alkahes The acid salt is formed oa
the basic mtrogen of the dimelhylamino
group attached to the number four carbon
atom The monosodium salt is formed by
reaction of the phenolic OH group in posi-
tion 10 with alkah The disodium salt of
these compounds also can be prepared In
this case, salt formation occurs at positions
10 and 12
Solubility. The free forms of the tetra-
cyclines are only slightly soluble m water
However, the hydrochloride and the sodium
salts are soluble m water but practically m-
soluble m acetone, chloroform and ether
Salts formed with other metals such as cal-
cium and magnesium are water msoluble
Incompatibilit}'. The tetracyclines are un-
stable m neutral and alkahne solutions
Therefore, it is not practical to use these
agents m the form of their sodium salts in
aqueous solutions Tetracyclme is somewhat
more stable to alkaline conditions than is
chlortctracyclinc, however, under more dras-
tic conditions, a similar degradation of the
molecule occurs * « ss s* been shown
that all of the tetracyclines are more stable
m solution at pH 2 5 than at either pH 7 or
9 when heated to 100° C for 15 mmutes and
that tetracyclme was less inactivated at all
three pHs dian either chlortetracydme or
oxytetraejelme * The hydrochlonde salts of
the tctrac)clmes are all stable m the dry
state
Tyrothricin
Tyrothnem is produced by the tyrolhnx
group of aerobic spore formmg soil bacteria
Bacillus brevis, B mesentencus, etc It is
composed of two crystalhzable polypeptides
known as gramicidm (20 to 25 % ) and tyro-
cidm (60%) These two substances can be
separated by treatment with a mixture of
acetone and ether Gramicidm is soluble m
this mixture and tyrocidm is insoluble
Tyrocjdm is beheved to be a cychc
polypeptide havmg a molecular weight of
approximately 2,500 and contammg two
molecules of aspartic acid, glutaimc acid, or
nithine, tryptophan, prolme, tyrosine, leu-
cme and valme, and three molecules of
<f-phenylalanme
Solubili^. Tyrocidm is strongly basic and
forms water soluble salts with hydrochloric
acid Gramicidm contains 6 tryptophan, 6
leueme, 4 vaUne, 4 alanme, 2 ^yeme and
2 unknown ammohydroxy compounds Both
ot polypeptides are nearly insoluble in
water, but tyrothnem is soluble m alcohol
Incompalibihty. Tyrothnem is used only
topically, smee it is too toxic for systemic
administration The gramicidm causes he-
molysis of the blood cells To be effective.
It IS necessary that the tyrothnem come m
direct contact with the offendmg organisms
VITAMINS
The vitamins are a very unportant group
of compounds m modem therapy and nutri-
tion Because most of the problems mvolving
their stability and mode of administration
have been solved, the practicmg pharmacist
does not encounter too many mcompatibih-
Ues in the dispensing of them. Many of the
previously exislmg difficulties have been
overcome by the various types of prepara-
tions which are readily aviffiable from drug
manufacturers However, some mcompati-
bihties are created when physicians attempt
to combme these preparations with other
drugs
The vitamins vary greatly m their chem-
ical composition On the basis of their solu-
bihties and the manner m which they are dis-
pensed, it IS convement to divide ffiem mto
nvo groups ( 1 ) the fat-soIuble vitamms and
(2) the water-soluble vitamins The fat solu-
ble group mcludes vitamins A, D, E and K.
The water-soluble group mcludes ascorbic
acid and those of the B-compIex
A complete discussion of all the com-
pounds possessmg vitamm activi^ and their
reactions is not appropnate in this chapter
Therefore, for the most part, only those re-
372 Incompotibiliijes of Orgome Compounds
actions and properties \Nhich contribute to
dispensing problems arc discussed.
Fat-Soludle Vitamins
Yilamin A (antiAcropblhalima vitamin)
pound originally designated as vitamin D
ivas found to be a mixture of lumisterol and
calciferol, of which only calciferol is anti-
rachitic The naturally occurring provitamm
D, 7-dch)drocholcstcrol, )ields vitamin Dj
'CH— C — CH— CH— CH — C*“CH — CH.OH
ViumiaA
C^CH,
oq::
I \ : I I
■ CH-C-CH-CH-CH-C-CH-CH1*CH“CH-C-CH-CH-CH-C-CH-CH
CH, C
p-Carotcac
IS a hi^ly unsatuxated alcohol found in the
nonsapoaihable fraction of fisb-liver oils and
animal fats The carotenoid pigments, known
as provitamins, are found m Die plant king-
dom The animal body is capable of conven-
ing many of these mto vitamin A Smec both
vitamin A and the carotenes arc highly un-
saturated, they are extremely sensitive to oxi-
dation. In the absence of oxygen, they arc
quite stable to heat Due to the relative ease
with which they undergo oxidation and
autoXidatiOD, care should be taken that the
emulsifying agents used m the preparation of
emulsions of dsh liver oils do not contam
oxidizing enzymes ** For example, the oxi-
dase* present m acacia should be destroyed
before the gum is used as an emulsifying
agent
Vitamm A and the carotenes are insoluble
m water, but they arc soluble m the nonpolar
solvents of ether, chloroform, carbon disul-
fide, benzene, petroleum ether and fats The
carotenes are practically insoluble in alco-
hol, however, vitamm A, due to the presence
of the —OH group, is alcohol-soluble
Vitamin D (aniirachitic vitamm) is found
m both plant and ammal tissues Crgostcrol
upon irradiation with ultraviolet light is con-
verted to vitamm D 2 (calciferol) The com-
*The oxidase is destroyed by drying the acacia
at tO}* to 105* C (Kieft, J P Pturm Wcckblad
76 1133. 1939} or by beaung aqueous preparaboos
lo 100* C
on inadialioQ This is identical with tlte
natural vitamm Dj of fish liver oils Tlie ani-
mal body apparently is capable of synthesiz-
ing vitamin O from various sterols At least
10 difierent provitamins D are now known
lo exist
Vitamins D are relatively stable to heat
and oxidation and, therefore, they are not
inacuvatcd by autoclaving at 120" C m the
absence of air In the presence of air they are
inactivated at this temperature Vitamm D 3
Vitamin Dj (calciferDl)
VUmmaDj
(calciferol), on heating at 160* lo 190® C
in the absence of air, yields pyrocalcifcrol
and isopyrocalcifcrol, both of which arc de-
void of antirachitic activity Vitamm D is
sUdilc to alkali, as shown by the fact that it
can be isolated from the nonsapomfiablc frac-
tion of fats All of the known viiamms D m
the pure state arc white, odorless ciysials
Vitamins 373
which are soluble m fats, ether, chlorofonn,
acetone and alcohol, but insoluble m water
Vitamin E is found in vegetable oils such
as wheat-germ oil, nce-germ oil and cotton-
seed oil It IS also present m leafy green and
yellow vegetables and fruits such as lettuce
and oranges Animal tissues contam only very
small amounts
0
Vitamm Ks
(2 methyl 3-difaniesyI 1 4-naphiho(juinone)
CH,
a Tocopherol
The tocopherols are water-msoluble but
are soluble m the less polar solvents such
as ether, chloroform and oils Four closely
related tocopherols of sunilar chemical com-
position, a, fi, Y and S, are known to possess
vitamm E activity In the absence of oi^-
gen, the tocopherols are stable to heat up to
200” C and are not affected by hydrochloric
orsulfunc acids at 100” C The tocopherols
are less resistant to alkalies and are destroyed
gradually when allowed to remain m contact
with alkalies for long periods of time Sufii
cient stability to alkali is manifested by the
tocopherols to make it possible to isolate
them from fats by saponification In an alka-
Ime medium, the tocopherols are especially
susceptible to oxidation This oxidation re
suits in a destruction of their vitamin E ac-
tivity Ultraviolet light also destroys their
activity Because of ^e ease wth which they
undergo oxidation, the tocopherols are effec-
tive antioxidants and are employed to pre-
vent the oxidation of fats The y isomer is
the most effective antioxidant, and the fi
isomer is more effective than the a isomer
The antioxidant activity is dependent on the
free phenolic — OH group which is not nec-
essary m the molecule for vitamin E activity
Vitamm K (antihemorrhagic vitamin)
occurs m plants and micro-organisms Two
I / *
CH-CH -CH -CH£-CH-CH
CH,
naturally occurring vitamins K are definitely
known Vitamm Ki is found m green plant
materials such as alfalfa and spinach, and
vitamm K 2 is found m most bactena The
bacterial flora of the mtestmal tract syn-
thesize large amounts of vitamm K that pro-
vide an important source m humans
Expenmentation has shown that vitamin
K activity IS not lost when a h)drogen re-
places the side chain m number 3 position
This compound, 2-methyl-l,4 naphthoqui-
none, also known as menadione, is official
m the US P and is used extensively m medi-
cme for its vitamm K activity Other substi-
tuted naphthoquinones are known to possess
vitamm K activity and have been used clmi-
cally Menadione sodium bisulfite, which is
a water-soluble derivative suitable for intra-
venous or mtramuscular mjection, is also
mduded m the US P
The naturally occurrmg vitamins K and
menadione are insoluble m water but soluble
m fats, ether, chloroform, acetone and pe-
troleum ether The vitamms K are thermo-
stable, but they are very sensitive to light
(sunlight, artificial hght and ultraviolet light)
and aUrahes Reduemg agents convert the
natural vitamms K and menadione to hydro-
qumonc derivatives
(2 meihyl 3 pbytyl 1 4-napbtboquxnOQO)
374 Incompohbilities of Organic Compounds
COr-'
0
MetudMoe
(2 methyl I 4-napbthoquiooQe)
Menadioite Soduio} BisuUite
Water-Soluble Vitamins
Ascorbic acid (cevitamic acid, vitamin C),
the antiscorbutic vitamin, is present to all
living plant cells and is found m increased
amounts m actively growing parts of the
plant Aniaa} tissues contain only small
amounts, but increased auanutics are present
in the organs and the endocrine glands (bver,
adrenal gland, thymus and pituitary) Hu-
mans are unable to synthesize the vitamin,
thus It must be mcluded in the diet Excellent
dietary sources include green vegetables,
bernes, apples and aims fruits The vitamin
IS also synthesized for commercial use
OH OH
Ascorbic acid is an odorless, white, crys-
talline compound which is soluble m water
(1 Cm in 3 ml ) and alcohol (1 Gm in
30 ml ) but msoluble in the nonpolar sol-
vents ether, chloroform, fats, etc Ascorbic
acid IS a monobasic acid, yields aad solu-
tions and readily forms salts with metab
This acid is a strong reducing agent, and in
aqueous solution it is readily oxidized and
inactivated by the ox}gca of the oir This
oxidative dcstmction of ascorbic aad talces
place rapidly m alialme solution, but it is
markedly decreased m aadic solution. Al-
kalies, oxidizmg agents, light, heat, riboQavin
and traces of iron and copper are all capable
of hastenmg the decom^sition of ascorbic
aad. In the dry crystalline form, ascorbic
acid IS relatively stable
p-Aminobeozoic acid (PABA) occurs in
the plant and the animal kingdoms m both
free and combined form Because of its wide
distribution in nature, no deficiencies duectly
attributed to it have been observed m hu-
mans Apparently, dictaiy sources and m-
testmal synthesis supply adequate amounts
of this essentia] metabolite
p Aminobeozo e Acid
p Ammobcnzoic acid is a stable colorless
substance which is soluble in water to the
extent of 0 5 Gm per 100 ml , freely soluble
10 boding water and soluble (1 10) in alco-
hol Its solubility m aqueous solution is in-
creased by both alkoh and mineral acids due
to the presence of both the carboxyl and the
ammo groups which enable it to form the
water soluble ionized salts
Diotm (vitamin H) is present in small
amounts m all higher animals Dietary
sources include liver, kidney, eggs, milk,
vegetables, grains and nuts It occurs m the
free state m plant sources and mamly as a
chemically bound compound m animal tis-
sues The s)nthctic product is available
commercially
0
kH HH
I I
CH -CH
I I
^CH-CHf-CH^CM,-CH,-CCOK
* Dwtin
Biotin IS soluble in water and alcohol and
insoluble m ether, chloroform and petroleum
ether The vitamin is relatively stable m
Vifamins
375
aadic and basic solution and to beat It is
inactivated by oxidizing agents
Choline (tnmethyI-;3-hydroxyethyIammo-
nium hydroxide) is a constituent of the
phospbobpids, sphingomyebn and lecithin
Dietary sources of the substance include egg
yolk, liver, bdney and the germ of cer^
grains This substance, which is included m
the B-complex, is a growth factor concerned
biologically with transmethylation reactions
m the animal body
CH.
1 »
CH.-N-CH,-CH,-OH
• I * *
CH,
Cholme
Cholme is a colorless, viscid, hygroscopic,
strongly alkalme hqmd, very soluble in water
and alcohol and insoluble m ether It readily
forms salts with acids (chlonde, bromide,
borate, picrate, etc ) The salts, which are
hygroscopic, are also soluble m water and
alcohol Aqueous soluaoos of the salts are
practically neutral
FoLc acid (pteroylglutaimc acid, "L caset
factor,” ‘ vitamin M,” ptendyl p-ammoben-
zoyl glutamic acid) is found m green leaves
(spinach, etc ), mushrooms, yeast, hver and
kidney It is also prepared synthetically
Therapeutically, fohc acid is used m the treat-
ment of various macrocytic anemias
COOH
OH COOH
Folic Acid
The folic acid molecule is composed of
a ptendyl group, p-ammobenzoic acid and
/-glutamic acid. In foods it is found in the
conjugated form containing additional mole-
cules of glutamic acid Folic acid is a stable,
)eIIow, crystalline substance which, although
only slightly soluble m water, is soluble m
dilute alkah and acid due to the present of
catboi^l groups and basic nitrogen m the
molecule However, it is destro)ed readily
by boiling in aad solution.
Inositol (hexah)droxy-c)clobexaae, meso-
mositol) occurs naturally as a normal cell
constituent in both plant and animal tissues
aad is prepared synthetically In nature it
occurs m many different forms Some mositol
occurs m the free state, but m plants it is
present mainly m the form of the hexaphos-
phate, m the hver it is combined with a pro-
tein and IS alkali labile, m soybean it is found
as a glycoside Only the optically mactive
form (meso mositol) possesses biologic ac-
tivi^
Inositol
Inositol possesses a sweet taste and is
soluble in water (approx 16 5 Cm. per 100
ml ) It IS insoluble m absolute alcohol and
ether Inositol is highly resistant to the action
of both acid and alkah
Nicotinic Acid and Nicotinamide. Nico-
tinic acid (niacm, PP factor, pellagra pre-
ventive factor, 3-pyndinecatboxyhc acid)
occurs m small amounts m all hving cells
Dietary sources mclude hver, yeast, wheat
germ and miJk Man is dependent on dietary
sources for mcounic acid, although consid-
erable amounts probably are contnbuted
through Its synthesis by the bactenal Bora
of the intestines In animal tissue it is found
not as mcotinic acid but as the amttfe A
small amount of mcotmamide (macmamide)
IS present m tissues in the free form, but the
majonty is present in the chemically bound
forms of co-enzymes I and II For commer-
cial purposes, mcotimc acid and mcotmamide
are prepared synthetically
O'""
NKOUaiC Acid NicoUnamide
Chemically, mcotmic acid is the ^-car-
box)hc acid of pyndme It is very stable and
may be heated without decomposition Nico-
tmic acid IS sbghtly soluble m water (approx.
1 65 Gm per 100 ml ) and alcohol (approx.
1 25 Gm per 100 ml ) and insoluble m
chloroform and ether The acid is readily
oh"
376 Incompalibilities of Orgonjc Compounds
soluble m dilute alkali and acid due to the
carboxyl group and basic nitrogen Vrhich
enable it to form the ^vatcr•soluble ionized
salt Destruction of nicotinic acid docs not
occur even when the compound is heated m
acid or alkaline solution
Nicotmamide (macmamidc) is very solu-
ble in both water and alcohol, but it is only
slightly soluble m ether In aqueous acid or
alkalme solution it is converted to nicotinic
acid by hcatmg
Pantothenic acid is present in all plant and
animal tissues Dietary sources mclude liver,
kidney, heart, tongue, yeast, eggs, muscle
tissue, rice bran and molasses In both am-
mal and plant tissue it is usually bound to
protein, only a small amount of this acid
occurs in the free form It is also prepared
synthetically
0 0
OK
Pantothenic aad is a white, odorless, crys-
tallmc powder which is rcaddy soluble in
water but insoluble m alcohol The vitamin
IS destroyed by heat, acids and bases In
aqueous acid or alkali solution it is bydro-
ly^ to alanmc and a-hydroxy-/7,^>di-
mcthyl-y-butyrolactone, as shown below
In higher animals, two other forms of the
vitamm which possess activity equal to that
of pyndoxme are the aimnc and the aldehyde
an^ogs (pyndoxamine and pyndoxal) It is
possible that other members of the B« com-
plex also exist ”
Pyndoxme is a colorless, ciystallme pow-
der havmg a slightly bitter taste It is soluble
in water, ^cohoT and acetone but only slighdy
soluble m ether and chloroform Due to the
presence of the basic mtrogen m the mole-
cule, It readily forms water-soluble lonizablc
salts with aads The bydrochlondc is the
form which appears on the market and is
most used It is soluble m water (22 2 Gm
per 100 ml ) and alcohol (1 1 Gm per 100
ml ) The aqueous solution of the hydro-
chlondc has a pH of approximately 3 2
Pyndoxme is stable to heat and acid but is
destroyed by light Because of the phenolic
—OH group m the structure, pyndoxme
shows many reactions of the phenols, eg,
It yields an orange-red color with feme chlo-
nde and undergoes air-oxidaiion m alkaline
solution
Riboflavin (vitamin B:, vitamm G, lacto-
flavin, 6,7-dmicthyI-9-(d-r-nbityl-)isoalIoxa-
zme) occurs m all living cells of the plant
and the animal kingdoms It is found cither
as the free vitamm, the phosphate, or the
adcmnedmuclcotidc phosphate Excellentdie-
HO-CH,-
0
#
•C — KM-CH-
CH,
Paalolheiue Acid
,0 «». ^ r wcCx ]
, CHOH-C— )w)J CHOH-C-0
g Alulae a Hydroxy g ^’dimethyl r-buiyrolactooe
Pyridoxme (vitamm D«, anti-acrodyma
rat factor, 3-hydroxy-4,5-di(bydroxymcthyI)-
2-mcthyl pyndinc) is present m both the
plant and the animal kmgdoms Dietary
sources include yeast, nee bran, wheat, corn,
molasses, fish, hver, milk, egg yolk, lettuce
and spmach The naturally occumng vita-
min IS present m the form in which it u bound
to protein Only small amounts arc found m
the free state is prepared synthetically, as
well
CM^CM C**/"*!
pyriloune PyndoxuuM
Pyndoul
taxy sources are heart, hver, kidney, muscle,
c^, milk, green leafy vegetable, whole gram
and yeast ^mmercial supplies of nbo^vm
ore obtained by the synthesis of the vitamm
Vifamins
377
Riboflavin k an orange-yellow crystallme
compound which is only shghtly soluble in
water (12 mg per 100 ml ) and ethyl alco-
hol (4 5 mg per 100 ml ) It is insoluble in
ether, acetone, chloroform and benzene Be-
cause of the basic nitrogen m the molecule.
It IS capable of forming such salts as the
monosuccmate, borate, phosphate and ace-
tate which are more water-soluble than the
parent compound These more soluble salts
have found use m pharmaceutical prep-
arations
Rcducmg agents convert nbofiavm to leu-
conboSavm, but this reaction is easily re-
versible The oxidation-reduction reaction
shown below is of great importance m the
function of nbofiavm nucleotide m cellular
respiration Riboflavm is quite resistant to
the action of oxidizmg agents
Thiamine hydrochlonde (vitamm Bi, thia-
mine, thiamme chloride, ancurm, antineuntic
vitamm, antibcnben vitamm, 4-methyI-5-/?-
hydroxy-eihyl-N-{[2 meihyl-4-ainmo-pyrim-
idyl-(5)]-methyl}tluazolium-ch]onde-hydro-
HCOH
HCOH
I
HCOH
I
CH|
CH,-
Ui9^elion in ^
oIkatifl« solution
■oufrol or ocid
solution
Lumallovin {e,7,9-tnfn»lhyl-
iso-oHosozino)
Y
Luimcl»<m»(6,7 duntlhyj-
oUoxotino)
RiboQavm is very soluble m aqueous al-
kalme solution by virtue of the acidic hydro-
gen of the imide group The acidic hydrogen
IS replaceable by sodium and, therefore, m
aqueous solution the water-soluble lonued
salt IS fonned However, the nbofiavm is
then quite unstable to light and heat In aque-
ous alkali, nbofiavm is converted by irradia-
tion to the biologically inacuve, fluorescent,
degradation product, lumifiavin In acid solu-
tion (pH 1 0 to 6 0), nbofiavm is quite
stable to heat, but it yields the macUve lumi-
chrome on irradiation
MCOH -fH, Y"
KOH
* HCOri
0 HO
LcuconboOatia
chloride) Thiamine occurs naturally m the
free form, as a protem complex, as a phos-
phorus protem complex, and as the pyro-
phtKphoric acid ester (cocarboxylase) Die-
tary sources of the vitamm mclude pork,
yeast, cereal grams, nulk, peas, beans, fruits
and nuts It is prepared synthetically for
commercial uses
TTuamme hydrochlonde i^ a white, hy-
groscopic, crystallme solid It is soluble m
water (lOO Gm. per 100 ml ), m alcohol
(1 Gm per 100 ml ) and glycenn (5 5 Gm
per 100 ml ) It IS insoluble m ether, ace-
tone, chloroform and oils Inasmuch os thia-
nune hydrochlonde is a basic mtrogenous
compound, it shon3 many of the reactions of
Riboflavin
378 Incompotibiliiies of Organic Compounds
the alkaloids and logicall) could be classified
with them It fonns insoluble compounds
vnUi tanmc, picric and phosphotungstic acids,
potassium mercuric iodide, mercunc chlo-
ride and iodine
In the dry ci)stallinc form, the vitamm is
stable, m stron^y acid solutions it is quite
stable, thus, aqueous solutions having a pH
of 3 S may be autoclaved at 120** C with-
out decomposition However, weakly acid
solutions (pH 5 0 to 6 0) are not stable to
heat In aqueous neutral or alkaline solu-
tions, thiamine h^drochlondc is unstable —
heat accelerates the decomposition It is,
thus, mcompatible with alkabes and other
basic substances Many mcompatibilities of
this nature anse when the vitamm is dis-
pensed m aqueous solution with substances
such as sodium phcnobarbital, alkali car-
bonates, bicarbonatcs, atrates, acetates, etc ,
all of which yield alkalme soluuons
Thiamine h)drochlonde u very sensitive
to both oxidation and reduction and it is,
therefore, mcompatible with oxidizing and
reduemg agents On oxidation, the vitamm
IS converted to the biologically inactive,
highly fluorescent thiochromc This reaction
cT
— it — C-CH, otteqUcft
CH CH^H
Thumma
TIuochrome
IS the basis for the photofluorometne method
of assay for the vitamm The reaction docs
not progress readily m strongly acid solution
(pH 2 0), but the fonnauon of the Uuo-
^ome is accelerated as the solution ap-
proaches neutrality (pH 7 0) After long
penods of time, small quantities of thio-
chrome are formed even m alcoholic solu-
tions of the vitamin.
Vitamm Dtj (Devidox, Cobionc, C)anoa>*
balamm, Dodex) is obtained commcraally
from the feimcntation products of such or-
ganami as Sirepiomyces grueus, S oUvaceus
and 5 aureofaaens In the normal daily diet.
It IS obtamed from foods containing animal
protem It IS considered to be an essential
nutritional factor required for normal blood
formation, neural function and growth The
main clinical uses for the vitamin at the
present time arc thus m the treatment of
pernicious anemia both with and without
neurologic complications, pam associated
with neurologic disorders and growth re-
tardation due to anim al protcm deficiency
The very complex chemical structure of
vitamm Bis has been elucidated'* and, as was
accurately reported, in previous work, it has
been shown to contain cobalt and a cyano
group** and has an cmpincal formula corre-
sponding to CesHgoNiiOuPCo The cobalt
IS present in the form of a coordination com-
plex m which the cobalt is trivalent and has
a coordination number of sue'* On acid hy-
drol)sis (6 N HQ, 100'’ C ), l-<*-D-nbo-
furanosido-5,6-dimeihylbcnzimid3zole is ob-
tained from the vitamin, whereas more
drastic conditions of acid hydrolysis yield one
equivalent of 5,6-dimctbylbenziimdazole
Other h)drol)sis products which have been
obtained from vitamm B |2 arc ammonia,
phosphonc acid and D-I •amino-2 propanol
Vitamin Bj- is soluble m water to the ex-
tent of 1 25 Cm per lOO ml at 25* C and
forms neutral, odorless and tasteless solu-
tions The vitamm is inactivated m aqueous
solution by strong acids and strong alkahes
The maximum pH range for stability in solu-
tion is 4 5 to 5 0 In this range, soluuons can
be autoclaved without significant loss of ac-
Uvity Vitamm Bia undergoes slow decom-
position on exposure to both ultraviolet and
visible hgbt It is stated to be unstable m
aqueous solutions containing acacia, alde-
hydes (such as vaniUm and those contamed
m synthetic fruit flavors), ascorbic acid, dex-
trose, ferrous gluconate, ferrous sulfate and
sucrose ** It is stable in the dry form at room
temperature provided that it is not exposed
to strong light for extended periods of time
REFERENCES
1 Abraham, B. P J Pharm St Phannaco!
3 264, 1951.
References 379
2 Adams, W L. J Pharmacol & Exper
Ther 75 340, 1943
3 Anker, H S , «/ a/ J BactenoL 5S 249*
1949
4 Antibiotics, p 8, London, Pharmaceutical
Press, 1952
5 Ibid,^ 61
6 Bohonos, N, er a/ Antibiotics Annual,
1953 1954, p 54, New York, Medical
Encyclopedia, 1953
7 Bond, O C., Himelick, R E , and Mac-
Donald, L. H J Am Pharm Ass (Set )
J8 30, 1949
8 Boothe, J H , er a/ Antibiotics Annual.
1953 1954, p 46, New York, Medici
Encyclopedia, 1953
9 Ibid . p 47
10 Booth, S H , e/ a/ J Am Cbem. Soc
75 4,621, 1953
11 Bourquelot, E J Pharm, Chim 19 473,
1904
12 Brecht, E A , and Rogers, C H J Am-
Pharm. Ass 29 178, 1940
13 Brink, N G , Kuehl, F A., and Folkers.
K. Science 702 506, 1945
14 Science 1/2 354, 1950
15 Brown, H C J Am Chem Soc. 67 378,
1945
16 Bury, C R J Am Cbem Soc 57 2,115,
1935
17 Cellulose Gum, Hercules Powder Co,
pp 2 9, 1949
18 Celmer, W D , Els, H-, and Murai, K.
Antibiotic Annual 1957 1958, p 476, New
York, Medical Encyclopedia. 1958
19 Chem &Eng Newsii 3487, 1955
20 Craig, L. C., Shedlovsky, T , Gould,
R G , and Jacobs, W A. J Biol Cbem,
J2S 289, 1938
21 Daubert, B F J Am Pharm Ass (Sci )
J3 321, 1944
22 Edwards, L. J Trans Faraday Soc. 46
723, 1950
23 Gilman, H. Organic Chemistry, >ol II,
p 1858, New York, Wiley, 1943
24 /iid,p 1844
25 Ibtd.<p 1609
26 Gis\oId, O, and Rogers, C. H The
Chemistry of Plant Constituents, p 203,
Minneapolis, Burgess, 1943
27 Goodman, L., and Gilman, A The Pbar’'
macological Basis of Therapeutics, p 1079,
New York, Macmillan, 1955
28 Ibid.f 169
29 GnU, F J Am Pharm Ass 21 765,
1932.
30 Hamilton, W F., George, M F , Simon,
E., and Turnbull, F M J Am Pharm
Ass (Sci ) 33 142, 1944
31 Hargreaves, G W J Am Pharm Ass
21 571,1932
32. Harned, R L., et al Antibiotics and
Chemolher 5 204, 1955
33 Hams, D A, et a! Antibiotics and
Chemother 5 185, 1955
34 Hu^t, E L J Chem Soc. 1 70, 1942
35 Hirst, E L, Jones, J K. N , and Jones,
W O Nature J43 857, 1939
36 Hoeksema, H , er af J A C S 77 6,710,
1955
37 Howard, M E Modem Drug Encyclo-
pedia and Therapeutic Index, ed 6, p 79,
New York, Drug Publications, Inc , 1955
38 Husa, W J Pharmaceutical Dispensing,
p 544, Iowa City, Husa, 1951
39 Ibid p 650
40 Ibtd.p 551
41 Ibid.p 458
42 Husa, W J , and JatuI, B J Am Pharm
Ass (Sci ) 33 217, 1944
43 Hutchings, B L., et al J Am. Cbem
Soc 74 3710, 1952
44 Jones, W G M > and Peat, S J Cbem
Soc 2 225, 1942.
45 Jordan, E. 0 , and Burrows, \V Textbook
of Bacteriology, ed 14, p 307, Philadel-
phia, Saunders, 1946
46 Kaezka, E. A , Wolf, D E., Kuehl, F A ,
and Foikers, K J Am Chem 7J
3569,1951
47 Kaezka, E. A , ef of J A C5 77 6404,
1955
48 Kedvessy, G Chem. Zentr II, 314, 1942
49 Kuehl, F A, Flynn, E. H, Holly, F W,
Mozingo, R , and Folken, K J Am
Chem Soc 68 536, 1946
50 Luder, W F , and Zuffanti, S The Elec
tronic Theory of Acids and Bases, p 120,
New York, Wiley, 1946
51 Ibid p 83
52 Lyman, R A Amencan Pharmacy, vol
2, p 196, Philadelphia, Lippincott, 1947
53 /iid.p 197
54 Ibid p 186
55 McElvain, S M The Characlenzation
of Organic Compounds, p 51, New York,
Macmillan, 1953
56 /Aid,p 51
57 Mclnick, D , Hoebberg, M , Himes, H W ,
and Oscr, D L. J BioL Chem 160 1,
1945
58 Merck Service Bulletin, Vitamin B 12 , Part
I, Pharmaceutical Information, p 2, 1953
59 /W.p 9
380 Incompatibilities of Orgonic Compounds
60 New and NonoOlctal Remedies, p 134,
Philadelphia, LippincoU, 1954
61 /W.p 112
62 Nuon, W Pharm J 167 213, 1951
63 Nonnan, A. G Diochem J 2S 200,
1931
64 Ibid
65 Osborne, C E, and DeKay, H G J Am
Phann. Ass (Pract ) 2 240, 1941
66 Osol, A , and Farrar, G E U S Dis
peosatory, p S68, Philadelphia, Ltppin
cott, 1950
67 Ibid p 27
68 Ibld.p 1043
69 Peck, R L., Craber, R P , Walti, A., and
Peel, E W I Am, Chem. Soc 68 29.
1946
70 Pfau.E Apoih Ztg 46 724, 1931
71 Pfeiffer, C, and Williams, H J Am
Pharm. Ass (Pract,) 8 572, 1947
72, Pharmacopeia of the Uruted States, Sa
tecnUi Rev , p 826, 1960
73 Pratt, L. S The Chemistry and Physics
of Organic Pigments, p 136, New York,
Wiley, 1947
74 Ibid p 137
75 Pratt R , and DuFreooy, J Antibiotics
p 193, Philadelphia, Lippincott, 1953
76 Remick, A, E. Electronic Interpretations
of Organic Chemistry, p 37, New York,
Wiley, 1949
77 Ibid p 235
78 Rosenberg, H R Chemistry and Physi-
ology of the Vitamins, New York, Inter-
science, 1945
79 Rowson, J M Quart. J &Yr Dk Pharm
10 161,1937
80 Taylor, T W J , and Baker, W The
Organic Chemistry of Nitrogen, p 31,
Oxford, Clarendon Press. 1937
81 Tool J S Quart J & Yr Bk Pharm
10 439, 1937
82 Ibid 12 573, 1939
83 Waller, C W , el al J Am Chem Soc
74 4981, 1952
84 Ibid. 74 A97S. 1952
85 Wesp, E F . and Erode, W R J Am
Chem Soc 56 1037. 1934
86 Weygand, C Organic Preparations
p 445, New York, Interscicncc, 1945
87 Wilson, C 0 , and Gisvold, O T Text-
book of Organic Medicinal and Pharma-
ceutical Chemistry, p 642. Philadelphia,
Lippincott, 1954
Chapter 1 1
Services to the Allied Professions
Roy C Darlington, Ph D *
INTRODUCnON
A major function of the practicing pharma-
cist IS his service as consultant to members
of the allied health professions Students,
teachers and practitioners of pharmacy are
constantly remmded that this is an important
objective of pharmaceutical educauon, and
many believe that it is bemg accomplished
However, the results of reliable studies and
surveys mdicate that the consultative service
rendered by pharmacists to physioans is
minimal, and m regard to practitioners of the
other health professions, it is practically non-
existent Thus, the present status of this
area of mterprofessional relations seems to
be at vanance with the objectives of pharma
ceuucal education and the vanous orgaiuza-
tions of pharmacy, unless certain basic facts
are taken mto account
A perusal of the Codes of Ethics adopted
by the American Pharmaceutical Associa-
tion m 18S2, 1922 and 19S2 reveals that not
until 1952 was there specific reference to
the relation of pharmacists to members of
any of the allied professions other than phy-
sicians ’ Furthermore, the statement.
The pharmacist willingly makes available bis
expert knowledge of drugs to the other health
professions
appeared first m the 1952 Code These facts
are especially significant because the A Ph A
Code IS generally accepted as the professional
Code of Ethics of the pharmacists of the
United States **
The curriculum of the representative col
lege or school of pharmacy, medicme, den-
Usiry, osteopathy, podiatry or vctcnnaiy
mecheme does not provide for adequate m-
* Professor of Pharmacy and head. Department
of pharmacy Howard Uoiveruty
strucUon m the proper mteirclationship of
the alhed health professions As a result, the
graduate pharmacist enters his profession
with madequale knowledge o! the need that
practitioners of the allied professions have
for the consultative services he has to offer
Similarly, graduates of the allied health pro
fessions (mcludmg medicme) enter their re-
spective professions unaware that it is the
responsibility of pharmacists to provide these
services These conditions do not contribute
to the attamment of the primary objective of
all of the health professions — that is, the
rendenng of maximum service to public
health
Data from two studies concerning the con
sultative service of pharmacists to the prac-
titioners of medicme and dentistry — the two
professions with which pharmacy is most
actively associated— will serve to mdicate
the extent of the consultative services re
ccived by the respondents A survey of
381
382
S«rvices to the Allied Professions
ph)siciam rc%’calcd that 54 pcrccntof theoph'
tbolmologists, 70 per cent o£ the otorhtnolar*
yugologists and 83 per cent of the general
practitioners bad never been approached by
a phannacist for the purpose of discussing
services available to physicians — this despite
the fact that 75 per cent of the physicians
wanted pharmacists to consult with them
conccmiog the prescribing of medications^'
Another study relating to dentistry showed
that 81 per cent of the participants had never
been approached by a pharmacist for the
purpose of discussing services to dentists'^
It may be argued that practicing pharma-
cists are adequately serving practitioners via
consultation mitiated by the latter This con-
tention IS not supported by data from a recent
survey In a study conducted by the author.
141 pharmacists were surveyed. Four of these
pharmacists were located m hospitals This
stud^ revealed that pharmacists m 137 stores
received approximately one request for in-
formation every 5 days Only 39 per cent
of the requests received required a profes-
sional education for answermg The hospital
phonnacists received less than four requests
per day and only 35 per cent of the requests
required a professional education for answer-
mg It IS mteresung to note that more than 7
per cent of the requests for information were
from dentists, podiatrists and doctors of
VCtermary medicine These data arc a port
of a national survey which reported on the
consulting practices of 481 pharmacies dur-
ing a l(^ay penod. The national survey
revealed that each pharmacy, on an average,
was consulted less than 5 times a week by
medical practitioners " The extent of the
services ^mg rendered to the practmonen
of homeopathy, osteopathy, podiatry and
vetermary medicine is easily gauged from
these statistics
Pharmacists feel that the compounding
and/or the dispcosmg of a prcscnption m-
volve a professional service and have a
tendency to rely on this service as the sole
basis for professional status On the other
hand, it is a fact that they are well quahlied
by training and experience to serve the addi-
tional function of consultant on drug products
to other health practitioners Indeed, the
pharmacist is tbs only pracutioncr whose
daily activities arc directly associated with
those of all other health practitioners m
xmnistenng to the pubhc health.
In order to assist the pharmacist in under-
standmg bis relationship with other prac-
tiuoncrs, It IS desirable that he know the
objectives, the qualihcatioos, the rcsponsibil-
ibes, the prerogatives and the limitations of
each of these The purpose of this chapter is
to impart such knowledge
MEDICINE
Medical Education
Medical education began m the United
States, as it did m Europe, with the ap-
prenticeship system By the year 1800, sev-
eral medic^ schools associated with um-
versities had been established Withm the
next century, hundreds of medical schools
were established in the United States How-
ever, m 1908, when Abraham Flexncr began
bis study of the schools of medieme m the
Umted States and Canada, only about 10
per cent of the praeuemg physicians were
graduates of medical schools "
When the Flexncr report was published
m 1910, only one of the 155 schools then
operating required a baccalaureate degree
for admission and only 16 required as much
as 2 years of college work. Presently, 76 of
the 86 medical schools m which students can
begin the study of medieme require at least
3 years of college preparation Ten schools
require the completion of a degree program
for admission *' In 1960, more than 80 per
cent of the students admitted to medical
schools m this country had completed 4
years of college
Medical Licensure
All of the Stales and the Distnct of
Columbia require a license to practice mcdi-
cme To qualify for a heense, a candidate
must be a graduate of an approved medical
school, pass a licensmg cxammation, and—
in 37 states and the Duinct of Columbia—
serve a 1-ycar hospital mtcmship As of
i960, 13 stales pcnmttcd hcensurc imme-
diately after graduation from an approved
medical school Twenty-one states and the
Distnct of Columbia require candidates to
Denlisiry 383
pass an exammation m the basic sciences to
become eligible for the medical licensmg ei-
ammation
All licenses to practice medicme are issued
by the states The National Board of Medi-
cal Ex amin ers also gives an exammation
which IS accepted by most states as a sub-
stitute for state exammation Most states do
not limit remprocity
Medical Practice
In 1960 nearly 40 per cent of all physi-
cians were located m the five states with the
largest populations New York, California,
Pennsylvama, Dlrnois and Ohio As a rule,
gener^ practitioners were distributed much
more widely than specialists, whose mem-
bers were concentrated m large cities *
The trend m medical practice is toward
specialization In 1923 the full time special-
ists represented only 1 1 per cent of the prac-
ticmg physicians m this country, by 1955
almost 40 per cent were specialists^* A
1959 survey of a selected group of medical
graduates (Class of 1950) disclosed that 63
per cent were m specialty practice, 33 per
cent were m geoerd practice and 4 per cent
were m research and teachmg This survey
— which IS still in progress — further revealed
that 78 per cent of a class of 196 1 62 mtems
mtended to enter specialty practice and only
18 per cent plaimed to go mto general prac-
tice The rcmaming 4 per cent planned
careers of research and teachmg
About SO per cent of those who plan to
specialize expect to practice mtemal medicme
or surgery Approximately 30 per cent plan
to practice obstetrics gynecology, pediatrics
or psychiatry, and 20 per cent mdicatc that
one of the other specialties will be selected **
There are 19 official Specialty Boards and
about 50 specialties or subspecialties of
medicme
The tendency toward mcreasmg specializa-
tion and the contmumg shortage of physi-
cians m the United Smtes are of real concern
to those who are mterested m the health
and welfare of our ever-mcreasmg popula-
tion If adequate medical services are to be
provided under such conditions, the tech-
mcol, the paramedical and the professional
groups associated with medicme must im-
prove and mcrease their services to physi-
cians
Practicmg pharmacists render an im-
portant professional service through the
dispcnsmg of prescriptions m greater num-
bers each year (More than 740 milhon
prescriptions were dispensed m 1961
They can provide an additional service of
great importance by actmg as consultants to
physicians — who, after all, are the prmcipal
presenbers
DENTISTRY
Dental Education
Educanon for the profession of dentistry
has evolved similarly to that of pharmacy
and the other health professions — ^from the
apprentice method with no formal academic
requirements to the requirement of a pro-
fessional degree preceded by presenbed
liberal arts education Since the establishment
of (he first school (the Balumore College of
Dental Surgery) m 1840, the profession has
developed from the level of apprenticeship
traimng to the level of a comprehensively
organized health profession ^
Dentistry has many national and local
organizations which pubhsb an abundance of
literature m the form of journals, scientific
papers and survey reports Some of the
important naUonal organizations vitally asso-
ciated with dental education are the Amen-
caa Association of Dental Schools, the Amer-
ican Association of Dental Examiners, the
NaUonal Board of Dental Exammers and
the Council on Dental EducaUon of the
American Dental Association.^*
The Council on Dental EducaUon is pres-
ently responsible for the accrcditauon of 47
dental schools, 34 dental hygiene programs,
4 schools for dental laboratory techmcians
and 306 mtemships and residencies It estab-
lishes educauonal standards for schools for
dental assistants and, recently, has devoted
much tune to the study of standards for cer-
Uficauon of dental laboratory teebmaans and
dental assistants
The 47 accredited dental schools m the
United States and Puerto Rico bav e a present
enrollment of almost 14,000, m 1960 they
graduated 3,253 students with the degree of
384 Services to the Allied Professions
tkictor of Dcotal Mcdicmc (DMD),
Doctor of Dental Surgery or Doctor of Dental
Science (D D S ) * “ Eighty per cent of the
graduates took the tbcorcticM cxaminatiOQ
adnunistercd by the National Board of Dental
Examiners The Board has issued more than
21,000 National Board Certificates since its
first examinations m 1934 At present, 35
state boards accept this cxammation ui iicu
of the states’ M-nttcn examinations, and it is
predicted that there will be 100 per cent
participation by candidates by 1970 and
100 per cent recognition by boards by
1980'®
Most of the graduates jomed the ranks of
approximately 90,000 active practitioncn,
and five of each six joined about 96,000 other
dentists who arc members of the Amencao
Dental Association They also joined one of
the 52 state societies m the 50 states and the
District of Columbia which are affiliated with
the American Dcotal Association ‘
Dental Practice
In Its development, dental research has
influenced dental practice considerably m
the areas of diagnosis, prcvcotion, restora*
uon and treatment As recently as the 1930*$.
dental practice was limited to relieving pam
and treating lesions of teeth and tissues of
the mouth Today, with a health'Coiiscious
public that IS much better informed concern-
ing disease and is rightfully demanding belter
health service, the dentist must be cooccrdcd
With the comprehensive management of oral,
facial and speech defects and with oral struc-
tures and tissues as they relate to the total
bcalih ot the mdrviiiual He mnsl not on\y
prevent the occurrence and the progression
of dcotal diseases, but also search for oral
pathologic changes that provide early indi-
cations of sj’stcmic disease *• In other words,
dcoUsts have the responsibility of providing
a complete health service to more and more
persons by preventive and restorative prac-
tices m all conditions that can be diagnosed
orally
The demand for dental care will coatinuc
to increase because of population growth,
improving economy, expanded dental iiisur>
ance programs and rising educational levels
In 1958, when almost 2 billion dollars were
spent by the public for dental care, nearly
two thirds of the population received no
dental care ° If these persons arc to receive
professional service, dentistry must become
more efficiently productive Dentists can ac-
comphsh this only by utilixing to a much
greater extent the auxiliary services of dental
hygienists, dental assistants and dental tech-
nicians Tbey also must use effectively the
services of the allied professions — medical
and pharmaceutical, prmcipally
Pharxwceutical Services
Recent activities at the academic and the
industrial levels indicate that improvement
m interprofessional relations ana pharma-
ceutical services can be expected There is
evidence that the pharmaceutical industry is
aware that the 1 1 million prescriptions
wntten by dentists m 1961 constituted ap-
proximately 1 7 per cent of the prescnptions
dispensed More important, the industry
realizes that this is more than double the
0 8 per cent reported for dentists by the
pharmaccuucal survey study in 1949 *’ It is
important that practicing pharmacists recog-
nize the significance of this trend m a pro-
fession whose practitioners may legally pre-
scribe for most condmons that can be
diagnosed orally The pharmacists must
demonstrate their competence as consultants
Ckimpctcncc lo this area requires that
pharmacists understand the terminology, the
therapeutic purposes and the dosage regi-
mens of general practitioners and dentists who
practice m a specialty The necessities of
dental therapy differ m many respects from
those of medical practice Because of these
dificicnccs, ihc dental presenpuon cannot be
expected to contribute a large part of the
doUar volume of prescription income More-
over, because the therapeutic needs of many
dental patients are short term m nature, as
few as 2 or 3 doses may be prescribed For
example, the dosage regimen for preopera-
Uve or postoperative treatment with drugs
IS usually of short duration Furthermore,
few such presenpuons arc refilled Pharma-
cists sometimes rc^rd a dental prescription
for 6 tablets or capsules or for 1 ounce of
an oral hquid as a ‘ nuisance presenpuon,"
but they should realize that such medication
IS a necessary adjunct to the rendering of on
adequate service to the pubhc health They
Dentistry 385
should utQize available house organs con-
cerning dental therapeutic agents They
should encourage their local associations to
sponsor joint meetings with local dental asso-
ciations They should imiiate and sustain
well planned consultative programs which
are desigued to make known the services
they are prepared to offer These programs
should be directed especially to general prac
titioners who represent 97 per cent of the
practicing dentists It is these dentists and
the specialists m oral surgeiy and pen
odontology who most frequendy use drug
therapy m their practices Information most
useful to the dentist follows
1 The procedure for procurmg a narcotic
registry number
2 The procedure for wntmg conventional
and special prescnptions (narcotic, etc )
3 The legal requirements concemmg oral
(telephone) prescnbing
4 The legal requirements concemmg the
procurement of amphetamine, barbiturate
and narcotic drugs for office use
5 The formulation of special drug com
bioations for use m dentistry
6 The availability of pharmaceutical
specialties applicable to dental therapy
7 The mdications and the contramdica-
tions for the use of specific drugs m dental
therapy
8 The assistance which is available m the
evaluation of curreody available pharma-
ceutical specialties used by dentists
In addition to servmg as consultants con
cermng prescnptions, pharmacists should be
famihar with the materials and the formulas
used by the dentists in their offices
PlIARMACEUTICAI, PREPARATIONS
Used By Dentists
Dentists purchase most of their office
supplies from dental supply bouses Many of
these products are promoted only to dentists,
and pharmacists cannot buy them at a pnee
less than that paid by the dentist Then^orc,
it IS impractical for pharmacists to serve as a
source of supply for such products It is
possible for pharmacists to ascertain the
needs of dentists m their neighborhood and
to prepare some of their office supplies How
ever, pharmacists can serve dentists best by
consultation concerning drugs which are
available for dental therapy In addition to
the previously mentioned sources of informa-
tion, there are booklets published by drug
companies which desenbe the drugs currently
promoted to dentists The number of such
publications can be expected to mcrease, be-
cause young dentists are wntmg more pre-
scnptions
Practically all of the presenpUon drugs
promoted to dentists are the same drugs that
are used by physicians For this reason,
dentists, m taking a case history, attempt to
learn what medicme — if any — the patient is
receiving By so domg, they avoid the risks
of prescnbing contramdicated drugs and of
duplicating medicmes The following are
some of the drugs which now are promoted
to dentists
Analgesics. The choice of an analgesic is
determmed by the seventy of the pam. The
foUowmg are presented most frequently
Salicylates A.P C capsules are used
alone or m combmation with codeine or an
nnlihittamifi ft
Non narcotic Analgesics Dextro propoxy-
phene — alone and m combination with com
pound aspirm or a tranquilizer and aspinn—
IS probably presenbed most often
Narcotic Analgesics Mcpendine hydro-
chlonde (f/5P) is preferred to morphme
for severe pam
Anti'infectivcs arc used therapeutically to
treat infectioas of the mouth Indications for
the use of these preparations are preopera-
tive and postoperative prophylaxis m patients
with a history of rheumatic fever, infectious
hepatitis, kidney disease or diabetes Al-
though sulfonamides and the broad spectrum
antibiotics are presenbed, pemciUm tablets
and lozenges are used most often The fol-
lowmg are examples of anti mfectives pre-
scribed by dentists
Pheaoi^metbyl penicillin tablets
) 250 tag.
Potassium pbenetbicillin tablets 250 mg
Phcnox)iQeffiyl pemciUin (115
mg ) with tnple sulfa tablets
(03 Cm.)
Buffered penicillin G tablets
(tZ-JJ*) 250 mg
PeniciUm lozenges 5,000 units
Tetracyclme h)drochIondc cap-
sules (t/3J» ) 250 mg
386 Services to the Allied Professions
iVnUbsslamsocs. Dcotists use anuhista-
mmes propbylacticaliy aod therapeutically
tn cases of drug allergy They prescribe them
also for use before and after oral surgery to
reduce postoperative edema aod pain and to
improve the healing process The rationale
for the latter use is based on demonstrations
that traumatic oral surgery mcrcascs the
bistamme content of the gmgiva and the
saliva Antihistamines prevent most of the
reaction of the tissues to the increased
amount of hutaminc Dquid or solid oral
dosage forms usually arc presenbed Since
the preparations promoted to dentists arc the
same as those used by physicians and are so
numerous and well Ijiouti, examples of these
are not given
Anti mllammafoiy Agents. Tissue damage
due to extractions and oral surgery is often
followed by excessive mflammation Such an
inflammatory response can be harmful aod
delay healing To prevent this reaction some
dentists use preoj^rauve and postoperative
treatment with corticosteroids This is a Iow«
dosage and short term type of therapy Phar-
macists who recommend these drugs to
dentists for use should also give them litera-
ture which explains the possible side cfTects
and the contraindications for use The fol-
lowmg pfcscnpuons are used by dentists ^
I Q
Prednisolone Tablets
(USP) 2.5 mg
#24
Sig 2 tabs pc ec h.$ for 2 days, then
J Ub g4h
2, n
Prednisone (U.SP) 2.5 mg
Chlorpheniramine moleate 2.0 mg
Vitonun C 75 0 mg.‘*
M fLTab #1
DTD #12
Sig Take 1 tab Li d
pc eths
IfjpnoUcs and Sedatives. Dentists use
barbiturates and nonbarbiturate C N S de-
pressants to calm pauents after operations
and to make them less apprehensive prior to
surgery Usually, quick acting sedatives are
used.
3 U
Secobarbital sodium capsules
Sig sh.s.pxn
4 n
Ethmamate tablets 0
Tab No VI
Sig 2 tab Vi b before appointment
(Ed note May be used tn the presence
of impaired liver or kidney
fuocuon )
5 n
Pentobarbital sodium (USP) gr iss
Aspinn (USP) gr v
M ft Cap #1
Mitle #X1I
Sig ) p r n for pam and oervousneu
Tranquilizers. Mild acting tranquilizcn of
the oeuroscdativc type are used with success
by dentists Unlike the barbiturates and many
other sedauves. drugs of this type alleviate
anxiety without lessening mental acuity
The mild tranquilizers arc especially useful
m the treatment of the apprehensive and
nervous patient who is having dJBcuIty m
adjusting to newly acquired dentures They
are also beneScial to many patients who are
startmg a long range restoration or rccon-
slnicUon program which will require dental
appomtments over a period of weeks or
months The anxieties of such patients arc
usuatfy a£fa)cd by therapy with (hugs such
as the following
6 n
PhcDaglycodot tablets 200 mg ”
No 36
Sig 1 lab Li d
7 «
Perphenazme tablels 2 mg
No 21
Sig 1 lab q 4-6 h.
Vitamins, Smee larger numben of the
populace arc seeking dental care aod because
dental canes, gmgiviUs, glossitis and stoma-
Komeopalhy 337
btis may be early climcal signs of nutritional
deficiencies, dentists are favorably positioned
to recognize the need for vitamm therapy
Muluviianuns, muluvilamins with min-
erals, and B complex with C vi tamins are
used m cases that mvolve metabolic stress
or significant dietary restrictions These cases
mclude patients with oral infections, those
who are undergoing oral surgery and those
who either are being fitted for dentures or
have acquired them recently Patients with a
prolonged clottmg time due to hypopro-
tbrombmemia often require vitamin K ther-
apy when undergomg tooth extraction or
dental surgery Among the vitamms presently
bemg prescribed by dentists are the fotlow-
mg
8 3
Multiple vitamin caps (therapeutic)
No 30
Sig 1 cap daily
9 3
B complex with vit Ccaps
No 36
Sig 1 cap 1 1 d
10 3
Multiple vitamin minerals caps (tbera
peutic)
#24
Sig i cap A M and P M
11 3
Menadione tablets (U S P ) 5 mg
No 10
Sig 1 tab 1 1 d
HOMEOPATHY
Development of the Profession
The homeopathic concept of medical prao-
bce was mtroduced m 1796 by the German
physician Samuel Hahnemann (1755-1843)
He hved to sec the profession practiced m
many countries of Europe, Asia, South
Amcnca and North Amcnca The practice
of homeopathy m the Umted States began m
1825 with the amval of Dr Constantme
Henng, one of Hahnemann s disciples Dr
Henng is considered to be the father of
Homeopathy m America. He established the
first college at Allentown, Pennsylvama
When this college closed, be founded the
Hahnemann Medical College m Philadelphia
This was the last college m this country to
discontinue the teac^g of courses m
homeopathy to medical students **
"niE Homeopathic Concept
TTus concept has its ongm m a ‘ Law of
Cure" found m the wmUngs attributed to
Hippocrates (ca 400 B C) “Through the
like, disease is produced, and throu^ the
application of the hke, it is cured.”*® It was
philosophy plus the results of his medi-
cal experiments which led Dr Hahnemaim
to announce the Law of Similars (simiha
simihbus curantur) as the Law of Chire and,
thus, launch the profession of homeopathy
The Present Status of Homeopathy
IN THE United States
Education. Homeopathy is not taught m
any msutution which grants degrees Pro-
fessional education m homeopathy consists
of a postgraduate course which is given each
year for two weeks at MiUersviUe State
Teachers College m Pennsylvama. Physicians
with the degree of M D , M B (British), or
D O (with unlimited practicing privileges)
receive certificates on completion of the
course Other practitioners may take the
course but they do not receive certificates
Homeopaths teach the course
The most significant efforts m education
have been made by the 1 1 Laymen’s Leagues
m as many cities These Leagues conduct
classes for laymen who are interested m
learning about homeopathy Instruction is by
a layman or tape recordings and is given m
10 weekly meetings
Organizabons of Homeopathy. There are
5 national organizations, 2 mtemational or-
ganizations and 19 state and sectional so-
cieties with homeopaths as members There
are also about 9 lay organizations working m
the mlerest of homeopathy The American
Institute of Homeopathy (busmess oifice m
Philadelphia) is the national organization
which represents the practitioners of homeop-
athy The Institute publishes a bimonthly
journal and is responsible for revision and
publication of the Homeopathic Phaimaco-
388 Services to the Allied Professions
pcia U S The American Foundation for
Homeopathy is the national organization
which directs the professional and the lay-
mens educational programs It also pub*
lisbes much of the literature of the pro-
fession
Practitioners of Homeopathy. Statistics
concerning practitioners have not been pub-
lished recently and Vierc not published in
1962 by the profession oc by the Govern-
ment However, it can be reported that in a
metropolitan area with a population of 2
million there arc about 25 practitioners of
homeopathy and one homeopathic pharmacy
Only two of these homeopaths pracucc true
homeopathy, the others use both * allopathic *
and homeopathic methods of diagnosis and
trcatmcnL The two genume homeopaths do
not presenbe and the others together wntc
an average of about 15 homeopathic pre-
senpuons per day These facts indicate that
homeopaths dispense rather than presenbe
Pharmaceutical Services to
Hosieopatiis
Dased on membership m state societies, it
appears that most of the pracutioners of
homeopathy arc located m the states of Cali-
fornia, New York and Pcnnsylvama Homeo-
pathic pharmacists provide presenpuon serv-
ices, but the predominant service is that of
manufacturing dosage forms to be dispensed
by the homeopath Those who practice only
homeopathy need no other services How-
ever, most homeopaths also practice ‘al-
lopathic medicine and, therefore, need ad-
ditional pharmaceutical services l^c rc^ar
pharmacist can provide consultative and pre-
senpuon services m regard to the modem
chemotherapeutic agents which most home-
opathic pharmacies cannot afford to stock
No profession can survive unless there is
a demand for its services The fact that
homeopathy has survived indicates that there
IS still such a demand As a consequence, it
IS necessary that information concerning
these services be available to mtercsted per-
sons A principal source of such inlormatioo
IS the Homeopathic Pharmacopeia of the
Umted States The revised 6ih edition was
published m 1941 and the revised 7ih edition
Is in the process of preparation. The Home-
opathic Pharmacopeia U S bos the same
governmental status as the f/ 5 P and serves
homeopathy m the same manner that the
V^P serves medicme and pharmacy All
drugs or drug combinations which arc olBcial
have been 'proved’ by testing on healthy
human beings There arc no antibiotics,
modem chemotherapeutic agents or injcct-
ables listed m the homeopathic pharmaco-
peia
'Die Preparatio*4 of Homeopathic
Dosage Forms
The principal vcbicLs used m the prepara-
tion of liquid and solid dosage forms arc
1 Alcohol (f/JP) — used to prepare tinc-
tures
2. Dispensing Alcohol (88% v/v)— used to
prepare dilutions from tinctures
3 Distilled Water — used to prepare solutions
of substances which have low solubibty in
alcohol
4 Lactose— used to prepare solid dosage
forms
Great emphasis is placed on the use of
fresh drugs in the preparauon of tinctures
and solutions The moisture content of the
drug IS calculated as a part of the menstruum
The unit of medicinal strength u the dried
drug The pharmacopeia recognizes the fol-
lowmg dosage forms
1 Tinctures. These are designated by the sign
« (zcn> reduced) to denote the strongest liquid
preparation Unless otherwise indicated, they
arc 10 per cent preparations
2 Aqueous Solutions. These are usually pre
pared ID 100 1 0 or 0 I per cent concentra
uons depending on the degree of solubility
3 Dilutions. These are prepared by diluting
Unctures with Dispensing Alcohol or by diluting
solid dosage forms with lactose The official
method of dilution is by the use of the decimal
scale whereby tbe original quantity of medi
cine IS djvid^ progressively by ten The first
decimal (IX) contains I/IO, the second dect
mol (ZX) 1/100, the third decimal (3X)
1/1,000, and the fourth decimal (4X) 1/10 000
of tbe original drug Some practitioners dcsig
naie thu s>stcm of dilution by using D1 for
I/IO, D2 for 1/100, D3 for 1/1,000, and D4
for i/10000 ccnccntraUoos. A few of the
fiomeopaihs still use the centesimal system of
dilution which was recommended and adopted
by Hahnemann In this system each dilution
contains 1/100 part of the preceding dduUon.
Osteopoihy 389
These dilutions are designated as follows* 1C
(1/100), 2C (1/10000), 3C (1/1,000.000)
etc
4 Tnturations These are tablets or powders
prepared by dilution with lactose
5 Tincture Tnturations. These are prepared
by adding the tincture to lactose, tnturating and
allowing It to dry Since these tnturations con*
tain oidy the dcohol soluble constituents of
drugs, they are different from tnturations pre-
pared from the drug To differentiate from drug
tnturations a minus sign is used above the fig-
ure denotmg potency, for example, IX (1/10),
2X (1/100) etc
6 Medicated Powders. These are prepared
by adding one part of a hquid preparation to
10 parts of lactose, tnturatmg and allowmg to
dry The strength of the medicated powder i$
one decimal more than the dilution used m its
preparatioiL
7 Medicated Globules These are made from
sucrose or lactose and they are medicated by
saturation with liquid preparauons The excess
of liquid is removed and the vial is inverted oo
a clean white blotting paper until the globules
00 longer cling together
8 Medicated Cooes or Disks These ore made
of caoe sugar aod egg albumen. They are
formed mto bemispbencal masses which are
designated according to the diameter of the
base lO millimeters The No 6 size, which is
most often used, will absorb about 2 drops of
Dispensing Alcohol They are used and dis
pensed in the same way as are medicated
globules *•
9 Homeopathic Frescnptions. The following
prescnptions were copied from die 1962 pre-
scription file of a homeopathic phannacy and
are reproduced exactly as written It is interest-
mg to note that tablet tnturates are presenbed
by volume as well as by number
5
Mercunus dulcis 6X
Phytolacca dec 6X equal parts
Disp TT 125
Sig 2 Q2H Today then
2Q3H
n
Thuja 12X
Disp T T 02 . u
Sig FourTabletsTID
li
Valeriana 0
Disp 30 cc
Sig gtt20HS
O
Phosphorus 30X T T
Disp oz. 1
Sig, Four tablets T I D
D
Glonoinum 6XTT
Disp 500
Sig 1 PRN
9
Carduus mar D2
Nux vomica D4
Valenana 0
Chehdon D2
aa ad 50 0 cc
Sig gtt 20 T I D ac
OSTEOPATHY
The Osteopathic Concept
The osteopathic concept os a system of
medical practice was introduced by Andrew
Taylor Still (1828-1917) who pracUced as
a physician and surgeon m the state of
Missouri From the time that he advocated
a different approach to health and disease,
and (or 18 years thereafter, osteopathy was a
one man profession In 1892 Dr Still
founded the first college of osteopathy at
Kirksville, Missouri The charter granted the
corpomUon (Amencan School of Osteop-
athy) and Its board of trustees the right to
coiffer the degree of Doctor of Medicme
(M D ) However, the degree Doctor of
Osteopathy (DO) was chosen
The osteopathic concept, as interpreted by
the faculty of the Ktrksville College of Oste-
opathy, emphasizes four general pnnaples
From ^ese are derived an etiologic concept,
a philosophy and a therapeutic technic which
are distmctive to osteopathy However, it is
emphasized that these are not the only fea-
tures of osteopathic diagnosis and treatment
The four principles are as follows
1 The body u a umt Though beterogeneoiu
in structure, the human body funcuons as a
umt in both health and disease Therefore, in
390 Services lo the Allied Professions
the managcmcQt of the patient, it is necessoiy
to consider the patient as a whole
2. The body possesses sell-regulatory nieeh-
anisms These mechanums are operative m the
A. Production of natural and acquired im
Qunity
D Hemostatic regulation of vital functions
C. Repair of damaged tissues
D Compensation for irreparable damage
3 Structure arui lunetton are reciprocally
inter related This relationship provides a basis
for the structural etiology of disease and for
the technics of manipulative therapy
4 Rational therapy is based on an under
standing of body unity, sell regulatory mech
anisms and the inter relationship of structure
and function All therapy is based on an evalua
Uon of the patient as a whole, and, although
special consideration is gisen to impairments
arising m the musculoskeletal system, rauonal
and appropnatc therapy may include surgery,
the use of drugs or any other properly recog
nued modality **
Osteopathic Education and Trainino
A oimimum of 3 years of prescribed
liberal arts educauoa followed by 4 years
of professional study m an approved college
of osteopathy are required for the de^e of
Doctor of Osteopathy (DO) Seventy per
cent of the 1961 entenog class had one or
more degrees Almost all graduates (more
than 99 per cent in 1960) serve an mtero-
ship m an osteopathic hospital that has been
approved by the Amencan Osteopathic Asso-
ciaiion for irauung interns Those who wish
to become certified as specialists must have
at least 5 years of training after service as
VQtcins The snccesslul compltncm of oral,
wnttCQ and practical cxatnmaiions, which are
administered by Certifying Boards, qualifies
them as specialists Presently there are 12
such boards **
There are now 5 accredited colleges of
osteopathy m this country In 1962 there
were approximately 1,561 students in these
colleges which have about 350 graduates a
year
Osteopathy in the United States
The first national organtzaDon (Amcncan
Association for the Advancement of Oste-
opathy) was formed m 1897, m 1901 it
changed its name to the Amencan Oste>
opathic Assoaatiom The Assooation u a
federaDon of divisional societies organized
within the states and the tcmtoncs of the
United States It publishes a scientific
journal, an annual directory, a code of ethics
and other publications for professional and
lay use *
Osteopaths are licensed to practice in all
of the states and the temtoncs m accordance
with the provisions of the heensmg laws The
various laws provide for one of three types
of licenses Alaska, Maryland, Mississippi
and Montana issue limited licenses which do
not permit the use of drugs or surgeiy
Arkansas, Georgia, Idaho, Louisiana, Minne-
sota, Morth Carolma North Dakota and
South Carolma issue limited licenses which
permit the use of either drugs or mmor sur-
gery The other 38 states and the Distnct of
Columbia usue unlimited licenses which
allow osteopaths the same pnvilegcs of prac-
tice that are granted medical doctors
(M D ’s) “
There axe more than 14,000 D 0 's in the
United States (one D O to every 17 M D ’s)
and more than 13,000 are m active practice
About 97 5 per cent of those in active prac-
tice arc located m the 38 unlimited states and
the District of Columbia, 2 0 per cent prac-
tice in the 8 states that permit the use of
either drugs or minor surgery, and 0 S per
^nt arc located m the 4 states that allow
only manipulative therapy More than half
of ^1 D O s ore located m S states, namely,
California, Michigan, Missouri, Ohio and
Pcrmsylvania. Most are in pnvatc practice
and arc relatively young, 7 per cent of them
are women fjcneral pracmiDners tend to
locate m small towns or cities The specialists
usually practice in large cities
Prescribing Practices
Although osteopaths were only 6 per cent
of the practicmg physicians in 1961, they
wrote more than 39 imllion new prescnptions
or about 12 per cent of all the new presenp-
Uoos ** About 88 per cent of the more than
13,000 practicing osteopaths need the same
pharmaceutical services required by physi-
cians (M D ’s) There arc no drugs or pre-
scriptions which arc unique to osteopathy
Practicing pharmacists have the responsibility
of cstabli^mg commumcation with the
osteopaths m their commumties These prac-
Podiatry (Chiropody) 391
titioners need the consultative services of
pharmacists even more than do physicians,
because many are not detailed by representa-
tives of drug compames to the extent that
physicians are
PODIATRY (CHIROPODY)
Chiropody, which hterally means the art
of treatmg diseases of the hands and the feet,
IS now used synonymously with podiatry The
approximately 8,100 practitioners who are
hcensed to practice in the 50 states and the
Distnct of Columbia deal solely with pre-
vention, diagnosis and treatment of diseases
of the feet Hospitals, city health depart-
ments and clmics of the Veterans Administra-
tion use the services of podiatnsts As com-
missioned officers m the Medical Service
Corps, podiatrists establish and supervise
dimes of podiatry in the several branches
of the Armed Forces In 1959, a study con-
ducted at an armed force trammg center re-
vealed that 6 per cent of all recruits were
referred to podiatrists for consultation and
treatment
PoDUTRic Education and Practice
In 1962, five colleges of podiatry or
chiropody were reported as being ac-
credited These colleges award the degree
of Doctor of Podiatry (Pod D ) or Doctor
of Surgical Chiropody (DSC) after the
completion of a course of study which m-
cludes 1 or 2 years of prescribed hberal
arts educaUon and 4 years of professional
education and training All podiatrists are
licensed to practice by board examiners who
administer qualifying exammations At least
4 states require the completion of a 1-year
internship after graduation Reciprocity is
available to practitioners m all but 16 of the
states^
State lavvs vary, but, as a rule, podiatrists
are licensed to diagnose and treat most foot
ailments by medic^, surgical, physical and
mechanical means They use roentgenopa-
phy, biopsy, unnalysis and biologic and blood
tests m diagnoses They perform various
tj-pes of surgery on the feet (no amputa-
tions) They do not treat systcime diseases
However, they arc qualified by academic
background to know when foot or lower-leg
pathology indicates the possible existence of
certam systemic diseases and the necessi^
for refeiT^ to a physician They do not ad-
minister general anesthetics but they mject
local anesthetics Thirty-five states and the
Distnct of Columbia permit podiatrists to
prescribe all forms of medication The other
states place varymg limitations on presenb-
ing pnvileges ®
Forms and Sources of Drugs
Used Bv Podiatrists
The National Formulary (N F XI) con-
tams the formulas for 17 specialty prepara-
tions used mpodiatnc practice These include
solutions, suspensions, ointments and a
powder They are representative of some of
the topical medicmes used by podiatrists
In addition to the formulas for special^
preparauons, the V F Y also included a list
of more than 100 drugs and preparations
used by podiatnsts All of the drugs neces-
sary to compound these formulas are stocked
by phaimacies, yet practically all podiatnsts
obtain their office supplies from supply
houses, pnmanly because pharmacists make
no effort to ascertam the needs of podiatnsts
Pharmaceutical Services Required
By Podiatrists
Educators and practitioners of podiatry
have slated that the use of prescnptions is
indispensable to a satisfactory and successful
practice of podiatry Therefore, the relation
between podiatrists and pharmacists should
be the same as that between physicians and
pharmacists Pharmacists should not pre-
senbe and sell medicinals for the treatment
of ailments of the feet which require diag-
nosis They have a responsibihty to assist m
educating the pubbe concemmg foot health
care This responsibihty dictates that phar-
macists should inform their customers of the
availabihty of podiatrists’ services, and they
should make referrals when necessary
Podiatnsts also want and need the con-
sultative services of pharmacists conceming
drugs and the wnting of presenpuons The
need for these services is so great that at
least one company sells booklets of presenp-
Dons to podiatrists These booklets contam
IS presenpUons, each of which is prmted
on a tear-off label The advertisement states
that this is a “dispensmg service "** This
392 Servicet to ihs Allied Professions
service IS obviously a responsibility of pnic>
ticmg pharmacists
The following arc examples of presenp-
tions used m the practice of podiatry
Analgesics. In most cases, podiatrists can
admmisler elTcctise local treatment to chnu'
nate foot pain However, there arc occasions
when oral medication is needed to relieve foot
pain ivhich may vary from mild to severe
For Rehef of Mild Pain
12. n
Acetophenetidin (U SP ) gr uss
Acetylsalicylio acid (U.SP) gr mss
Caffeine (0^ P ) gr ss
MfLCap No l.DTD No 24
Sig 11 q 4 h p r □ for pain
13 n
Pentobarbital sodium (USP) gr ss
Acctylsalicylic acid (USP) gr v
M ft Cap No 1
MitteNo 21
Sig 1 q 4-S h. for pain
For Relief of hfoderate Pain
14 n
Acetopbeaclidia (U S P ) gr iiss
Acet)UaIic}Iie acid (USP) gr mss
Caffeine (U.S P )
Codeine phosphate (U-S P ) aa gr $$
MftCap No l.DTD No 16
Sig I not oftencr than q 4 h pjrn
for pain
15 n
Ethoheptazine citrate 75 mg
Acetylsalicylic acid (U S P ) 325 mg
Mft lab No 1. DTD No 24
Sig 1 or 2 tabs. 3-4 times daily for paio
For Relief of Severe Pain
16 U
Mcpcndinc HG Tablets
(USP) lOOmg
No 9
Sig. Tab I q 6 h. p r n. for pain
17 n
Methadone HG Tablets
(U.S P ) Urns
TD No 10
Sig Tab 1 not oficner q 6 h p r n for
pain
18 n
Dextro propoxyphene 32 mg
Acetophenetidin (USP) 162 mg
Acctylsalicylic acid (U.SP) 227 ms
Caffeine (USP) 32 4 mg
Mft Cap No 1, MitteNo 20
Sig Cap 1 or 2 q 6 h for pom
19 1>
Levorphanol tartrate tablets
Sig 1 q 8 h
Sedatives and Hypnotics Patients who arc
apprehensive and restless pnor to, during or
after treatment or surgery may need the relief
afforded by these drugs
20 n
Pentobarbital sod Cap (USP) gr iss
No 6
Sig 1 cap Vi h before appointment
21 n
Secobarbital sod Cap (USP) gr iss
No 12
Sig I h s for sleep
22 n
GluIcUumide Tab (N F ) Q 5
No 10
Sig 1 tab ut diet p r n
<\nli mfcclncs Anubiotics and suifona
nudes arc used to treat infections of the feet
and the lower port of the legs They arc also
used prophylactically in foot fractures or foot
surgery, with diabetic patients and those who
have a history of rheumauc fever infectious
hepatitis or recent pulmonary disease A1
though the sulfonamides and the broad
spectrum anubiotics are prescribed, the oral
preporauoDs of pcniciUm arc used most fre-
quently The following arc examples of prep-
arations prescribed by podiatrists
Veterinary Medicine 393
23 5
Buffered peniciUio G Tabs
(U^P) 125 mg
No 12
Sig lq4h between meals
24 5
Potassium phenethiciUm Tabs 250 mg
No 12
Sig 2 stat, then 1 q 4 h q i d
25 n
Erythromycm Tab (USP) 250 mg
No 12
Sig 1 q 6 h
26 U
Phenoxyinelhyl penicillm for
oral suspension (USP) 60cc
Sig lOcc tid Ih ac
27 D
Tetracycline HQ Caps
(USP) 250mg
Sig 2 caps q i d
28 0
Triple sulfa Tabs 0 5 Cm
No 36
Sig 4 tabs stat , then 2 q i d with full
glass of water
VETERINARY MEDICINE
O? 'SHE PROf ESStOH
Vetermary medicine is a separate, self-
governing profession with its own system of
education, licensure and organization As an
organized medical profession it is relatively
young, the first veterinary college m the
United States having been established m
Philadelphia m 1854 By 1900 about 30
vetermary schools had been organized, and,
with the exceptions of the statfi-supporied
institutions of Iowa, Ohio, Washmgton State
and Ciimcll, New York, they were pnvately
supported More than 10,000 vetennanans
were graduated from the pnvately-supported
colleges before the last one — located m
Washmgton, D C— closed m 1927 At pres-
ent there are 18 vetermary schools m the
United States and two m Canada, all are
associated with a college or a umversity and
arc accredited by the American Vetermary
Methcal Association ( A V M A )
Veterinary Medical Education
Ihe 18 schools and colleges of vetermary
medicme m the Umted States have their roots
m the schools of agriculture Most were out-
growths of departments of vetermary science
With the exception of Tuskegec Institute and
the University of Pennsylvama, all of the
vetermary colleges and schools are located
in land-grant or state-operated institutions
Seven of the state-supported vetermary
schools have been established smee the end
of World Warn
Smee 1949 all of the colleges have re-
quired a minimum of 2 years of college edu-
cation for entrance to the 4-year professional
program. Although mdividual courses vary,
all professional cumculums mclude 2 years
of basic sciences and 2 years of climcal vet-
eruary medicme and surgery Most of the
colleges are of comparable size and no col-
lege admits more than 75 students m a feesh-
fflan class In 1961 there were approximately
two applicants for each available place and
about one fifth of those admitted had ac-
quired advanced degrees prior to admit-
tance*
In most colleges the students are requned
to gam practical expenence by working at
least one summer session with a practitioner
Several colleges have internship programs
which students must complete before they re-
ceive degrees Each year about 900 graduates
receive the degree of Doctor of Veterinary
Medicme (D V M or V M D ) from the 20
colleges About 10 per cent of the vetermary
students, many facul^ members and others
engaged m research are domg graduate work
m the fields of anatomy, microbiology,
pharmacology, physiology, pubbe health and
vetermary pathology On the completion of
these studies they receive the degree of
Master of Science or Doctor of Philosophy
Veterinary Medical Licensure
Each state has an examining board which
administers written, oral and practical cx-
anunations to candidates for licensure There
are about 25 states that use the objecuve tests
394
Servicet to tho Allied Professions
\stuch are prepared by the National Board
of Veterinary Medical Examiners (estab-
lished m 1950) and the Professional Ex-
amination Service of the Amencan Public
Health Association. It is expected that in-
creasingly more states will use these exami-
nations Other staustical data concemmg the
profession of \etennaiy medicine are shown
in Table 85
Table 85 Data Coscermnq Veterinary
Medicine IN 1962*
Vetcrinonam m the Uzuted States 21,954
Vetennonans m Canada 1,597
Membership in AV MA. 16,131
Vetennonans m general practice 501%
Vctcnnarians in small animal
practice 22 1%
VeCennanam in other types of
practice 3 2%
Vetennaruns m teaching and
research 5 6%
Vetennanans in regulation, nulilaiy
and public health 1 1 2%
Vetennanans in miscellaneous
activities 7 8%
Number of ammol hospitals in the
United States 4,000
Number of animal hospitals that
specialize m or include small ani-
mal treatment 3,000
Number of families in U S that
own one or more dogs 17,900,000
Number of families lo U S that
own one or more cats 1 1300,000
Number of students who entered
vetennary colleges in 1961 1,104
Total number of students enrolled
in vetennary colleges for the aca-
demic year 1961*1962 4,008
Total number of women students
enrolled in 1961-1962 157
*AVMA Bulleun Vetennary Roundup d. No
1 , 1962 .
Tub American Veterinary Medical
Association (a V.hf A)
The A V.MA , which is the professional
organizatioa of Amcncon and Canadian vet-
ennonons, was founded ss the United States
Veterinary Medical Association on June 9,
1 863, in New York City. It assumed its pres-
ent name in 1898 The Association is com-
posed of 63 constituent associations repre-
senting vetennanans in the 50 states, the
Canadian proving, the U S temtones and
possessions, the Federal Government and
the Armed Forces The Association has its
headquarters in Chicago and maintains a
bureau m Washmgton, D C
The Association publishes the Journal of
tfae Amencan Veterinary Medical Associa-
tion (semimonthly), The Amencan Journal
of Veterinary Research (bimonthly) and a
Directory (annually) Special^ Boards m
veterinary mcdicmc recognized by the
A V M A are the American College of Vet-
erma^ Pathologists, the Amencan College of
Laboratory Animal Medicine and the Ameri-
can Board of Vetennary Public Health
Veterinary Medical Practitioners
Most vetennanans are currently engaged
m the following fields of work
1 Pnvatc practice (about 66 per cent)—
large animal, small animal or mued practice
2. Covernment service (about 14 per cent)
— federal (domestic or foreign), state and local
(county or municipal) work m animal disease
control, research and publie health areas
3 Military service m the Army or the Air
Force Veterinary Corps (about 4 per cent)
4 Teaching, research, or both (about 43 per
cent)
5 Commeraal employment (about 13 per
ccDt)^ — those engaged in the development, the
production, and the testing of biologic
products **
Services Required From Practiciso
P lURMAClSTS
Pet vetennanans have the greatest need
for tfae services of practicing pharmacists
These practitioners serve persons who arc
emotionally motivated to seek care for their
pets and, therefore, readily accept presenp-
tiOQS, whereas fanners are pnmarily inter-
ested m the dollar value of the onunals which
must be treated. Smee most form calls are
for the treatment of emergency illnesses or to
gisc mjcctioos for immumzatioa, the medi-
cines arc usually administered by seten-
oanons Despite these facts, pharmacists con
provide some services if satisfactory com-
munication is established Pharmacists should
especially know that the USP, the NF,
Veferinary Medicine 395
and other pharmaceutical tejctbooks are is-
cludmg mcreasmgly more mfonnation coc-
cenuag drugs used by vetermanans
Pharmaceutical Preparations Used by
Farm Veterinarians
Biologicals are the most unportant o£ the
mjections used by farm vetermanans The
quahty of these preparations is controlled by
the U S Department of AgncuUure through
Its Animal Inspection and Quarantme Di-
vision of Agncultural Research Service,
USD A Approximately 125 kinds of vel-
ermary biologicals were produced in 1959
by 65 companies Vetennarians use anti-
sera, vaccines, bacterms, antitoxms, toxoids
and other mjectablcs m the prevenuon, the
diagnosis and the treatment of diseases of
animak Examples of die preparations used
are
1 Antisera
Anti anthrax serum
Antibacterial
ongm)
Antibactenol
serum
bovine
(bovine
serum
equine
(equine
ongm)
AnU blackleg
serum
bovine
(bovine
origin)
Hog cholera antiserum (porcine ongm)
Swine erysipelas aatisenim (equine origia)
2 Antitoxins
Botulmus antitoxin (Types A, B and C)
Tetanus antitoxin
3 Baeterins
Mixed bactenn, avian (chicken formula)
Leptospira pomona bactenn
4 Toxoids
Tetanus toxoid (alum precipitated)
5 Vaccines
Anthrax spore vaceme
Rabies vaccine
6 Diagnostic Antigens
Leptospira antigen
Pullorum disease antigen, stained, poly-
valent
'Diberculm (intradcrmal)
Pharmaceutical Preparations Used by
Pet Veterinarians
The oral and the topical medications used
to treat pets are similar to or identical with
those used m the treatment of human beings
However, the doses and the nomcncUituie
of many of these drugs differ In addition,
pharmacists should be aware of the unusual
reactions of cats to certain drugs
The dosage regunen of animals is deter-
mined by body weight As a rule, the dose
for cats is one half that of the human adult
and the dose for the average dog (about 45
lbs ) IS the same as that for the adult human
being Cats are very sensitive to the alkaloids
of opium and their derivatives, and phenolic
compounds are usually not apphed topically
Ihe following presenpUons are representa-
tive of the compositions of pharmaceutical
specialties promoted to pet velennanans
Medical
Category Prescription Remarks
Anuhistamimc
Prophenpyndamine maleate
lOmg
Used for eczema, pruntis.
Sulfur
20 mg
mange and other der-
dl methionine (N F )
30 mg
matoses
M fL Cap No 1
MiUeNo 24
Sig Give one Li d
Codeine phosphate (U S P )
gr IV
Used to treat coughs and
Expectorant
Sodium citrate (U S P )
oiss
colds
Anunomum chlonde (U S P )
gr XX
Ipecac syrup (U^ P )
Tolu balsam syrup (U^ P )
3u
qj ad
Sig 3 1 q 4 h
Sedauve-
F.ihylrnnrnhme hydrochlonde
Used to treat broocIuUs
Expectorant
(NF)
gr V
and tracheitis (should
Potassium guaiacolsulfonate
not be administered to
(NF)
3ss
cats)
396
Services to the Allied Professions
Medical
Category
Scdauvc-
Expcctoranl
Dermatologic
Dermatologic
Dermatologic
Antibistamiuc
BroQchodilator
Antisposmodic
Oronchodilator
Gcnatnc Formula
PRESCRimOS
Potassium citrate (N P )
Citnc acid (U^ P )
Alcohol (USP)
Orange s) rup (U^ P ) q s ad
Sig o I tud
Iodoform (N P )
Tannic acid (N P )
Potassium alum
Bone acid (Ui> P ) oa
Exsiccated ferrous sulfate
(USP)
Talc (U S P ) qj ad
Sig Use topically as directed
Neomycin sulfate (U^ P )
Pantothenylol
Hydrophilic ointment (USP)
q s ad
Sig Apply to affected area b i d
Bismuth subgallate (N F )
Oil ofeade(USP)aa
Resorcinol (USP)
Bumulb subniirate (N F )
Calamine (USP)
Zinc oxide (USP)
White ointment ( U S P ) q s ad
Sig Apply as directed
Phenylephrine HCKU^P)
Chlorprophenpyndamme ma
leate
Dihydrocodcinone bilartrate
(NF)aa
Chloroform (U^P)
Menthol (USP)
Alcohol (USP)
Aromatic cUxir (U.S P )
q s ad
Sig lOcc Lid
Dextromorphao HOr (N F )
Mcthoxyphcnamine KCl
Sodium citrate (U^ P )
Cherry syrup (U^ P ) qj ad
Sig 2cc.q4h
Dicthylstilbestrol (U^ P )
McibylCestostcrone (U^ P )
Vitamin B 13
Thiamin HCl (U^P)aa
Nicotinamide (U^ P )
Riboflavin (USP)
Pyndoxine HQ (US P )
Calcium pantothenate
(USP) aa
Cherry syrup (US.P) q.sjd
Sig Give 5 cc. Lid
5tss
5$s
5^
5>v
1^0
3%
5%
6%
5 *
os%
1 %
300
1%
9 %
to%
17%
300
10 %
120
008
04
004
2
3
6 :
90 j
1 8 mg
360 mg
18 0 mg
90 Drag
9 0 mg.
900cfc
Remarks
Used to control capillary
bicedmg
Used for supcrllcial sbn
infections or abrasions
For nuDor sbn conditions
or first degree bums
For respiratory conditions
complicatcdbycongcsted
mucosa, bronchospasm,
and cough (use with
caution for cals)
For cough associated with
bronchial constriction
Used m genatnes rccom
mended for prcopcrativc
and postopcraihe use
also for weakened and
deficient states due to
any cause
Vetennary Medicine 397
Medical
Category
Prescription
Remarks
Hematinic Vitamin
Desiccated liver (N F )
Ferrous gluconate (U S P )
Thiamm HCl (U S P )
Riboflavin (U S P )
Nicotinamide (U S P )
Mft Cap No I
TD No 36
Sig Give 2 b 1 d
0 250
0 120
0 003
0 001
0 DOS
Used for anemias, malnu-
tritioD and anorexia, also
as a tonic following re-
moval of intestinal para-
sites
Anti arthritic
Metfaylprednisolone Tab
No 24
Sig Give one 1 1 d for 4 days,
then one bid
2 mg
Recommended for use in
certain skin, otic and
ocular diseases, also used
in allergic and stress
conditions
Anti infective
Potassium penicdlm G (USP )
200 M units
Sulfadiazine (U S P )
Sulfamethazme (USP)
Sulfamerazine (USP)
M ft Cap No 2
D T D No 12
Sig One Capsule V6 h ac
I bid
0) 167
0 167
0| 167
Used for treatment of ab-
scesses, poeumoma and
other suscepbble infec-
tions
AnU infective
Tetracycline HCl Capsules
(USP )
#16
Sig Give two capsules q 6 b
125 mg
Used to treat pentomtis,
hemorrhagic septicemia,
parotitis, otitis media and
otherinfectious processes
Gastrointestinal
Agent
Neomyem sulfate (USP)
Sulfaguanidioe (N F )
Sulfadiazine (USP)
Sulfamerazine (U S P ) aa
Kaolm (N F )
Fectm (N F )
Peppermint water (USP)
q s ad
Sig 5 1 b 1 d
gr V
3 11
gr vm
5 VI
gr vm
Used for diarrheal condi-
tions associated with in-
fectious enteritis, dis-
temper, leptospirosis and
parasitic mfestation
Gastrointestinal
Agent
Bismuth subcarbonate (USP)
Phenyl salicylate (N F ) aa
Zinc phenolsulfonate (Nj^ )
Pepsm (N F )
Methylcellulose (U S P ) %
Lactated pepsin elixir (N J )
qsad
Sig Give 2 to 4 cc. Li d
0 5
0 3
1 0
120 0
An antacid, astringent and
protectant for use in
conditions where gastro-
intcsunal imtation exists
Gastrointestinal
Agent
Aluminum hydroxide gel
(USP)
Sig 5to lOcc q2-4h.
240 0
Used in treatment of pep-
tic ulcers (gastnc and
duodenal), idso for the
relief of symptomatic
hyperacidity
Gastrointestinal
Agent
Pentobarbital sodium (USP)
Belladonna extract (N F )
M fL Capsules No 20
Sig . Cap 1 U-d.
013
0|2
Used in the treatment of
spastic states of the gas-
trointestinal, the bOury
antt the unnaiy tracts
398
Servicet lo the Allied Profesiion*
Medical
Category
Prescwptiom
Remarks
Bronchial
Anil asthmatic
Ammoph>lline (U S P )
Dried aluminum hydroxide get
0
I
Used to treat asthma, as*
cites, edema and cardiac
Tranquilizer
(USP )
Phenobarbital (U.S P )
DTD No 15
Sig Give 1 tab daily
Chlorpromazinc HCl Tablets
0
0
15
015
dyspnea
For use in treatment of
(USP)
MittcNo XII
Sig Tab lql2h
25i
mg
hystena car sickness and
vomiting
Tranquilizer*
Prednisolone (USP)
5 mg
Used in the treatment of
Corticosteroid
H)droxy 2 ine HCl (N F )
M ft Cap No 1
MittcNo 12
Sig Cap Ibid for 3 days
then 1 daily
10 mg
a vanety of allergic con
ditions complicated by
anxiety and tension ex
amplcs are chrome urti*
coria keratitis prunus
kennel cough, eczemas
and kcrato-conjunctivitis
Ophthalmic
Hydrocortisone acetate (USP)
1%
For the treatment of oeu
Preparauon
Neomycin sulfate (USP)
05%
lar inflammation and in
Benzolkonium chlonde
Phcnacaine HCl (N P )
H) droph die petrolatum (USP)
qsad
(Dispense m ophthalmic tube)
Sig Apply ou bid
1 5000
1%
150
fcctioo
Muscle Relaxant
McphcncsmTablcts (N F )
#21
Sig Give one U d
500 mg
For treatment of spastic
eonditions associated
with disease or injury to
a joint also used in
chorea, arthnUs and
sU>chmnc potsomog
REFERENCES
1 Adams, J E Abstract of State Laws,
p 15, Washington, DC, Amcncan Fo
diatiy Association, 1961
3. IbiJ p 37
3 A V M A. Bulletin Velennaiy Roundup
6 No I, 1962
4 Breuster, R. E Coraers in Osteopathy,
Guidance Leaflet No 23, p 8, U S Gov
emment Pnntuig Ofllcc, Wastunglon,
DC, 1961
5 Bulletin No 1300>71, p 2, U S Govern
ment Printing Oflice, Wo^ngton, DC.
1961
6 Bureau Report Summary of survn of
dental practice, D,A 62 765, 1961
7 Burlage, H ^f , Lee, C and Rising,
L. W OnentaiioQ to Pharmacy, p 271.
New York, McGraw Hill, 1959
8 Committee Report Dental education,
J ADA 62 95,\96\
9 Constituent societies aflUiated
with A Dj\ , Ju\ D A 63 179,1961
10 Couned Report Growth of the National
Board, J A D^ 65 410,1961
1 1 Darlington, R C Improving prescription
practices, 111, J N Ph A 2 26 1955
12 • - - - The status of dental therapeutics
in dental schools and colleges, J N Fh A
S 30, 1958
13 Deno R A Rowe, T D, and Brodie
D C The Profession of Pharmacy, p 9
Philadelphia, Lippincott, 1959
14 Division of Operational Studies, A^ M C
Current trends in career choices among
medical graduates J Med Educ 3? 239,
1962.
15 Flconcr, A Medical Education m the
Veterinary Medicine 399
Umted States and Canada, p 3, New York,
The Carnegie Foundation for the Ad-
vancement of Teaching, 1910
1 6 Furr, E B Pnvate communication,
March, 1962
17 Furr, W B , and Furr, E B Private com-
munication, June, 1962
18 Green, J M The Heart of Homeopathy,
p 24, Washington, D Q, American Foun
dation for Homeopathy, 1961
19 Ibid ,p 4
20 Hillenbrand, H Dentists will write 18
million Bs by 1970, APP 28 23, 1962
21 Hockstein, E S The role of the podiatrist
15 the naval service, J,APA. 51 488,
1961
22 HoUinshead. B S The Survey of Den
tistry, p 239, Washington, D C , Ameri-
can Council on Education. 1961
23 Ibid.p 241
24 lbid,p 414
25 Ibid, p 565
26 Ibid.p 95
27 Homeopathic Societies, JAIH 55 D,
Nos land 2, 1962
28 Information and Statisucs Bulletm, Amen-
can Osteopathic Association, Chicago,
1961
29 Lavelle, M B Pnvate communication,
June, 1962
30 ' Pnvate communication, January,
1962
31 Miller, C E An mquuy mto medical
teaching, J Med Educ 37 185, 1962
32 Mills, L W Educational Supplement,
J^O A , 61 393, 1962
33 Mordell, J S The Prescnption Study of
the Phann-iceuCscsl Survey, p 20, Wash-
ington, D C , Amencan Council on Edu-
cation, 1949
34 Myers, T J Advisory Board of Osteo-
pathic Specialists and Board of Certifica-
tion, J AO A, 60 577, 1961
35 National Formulary, 10th ed, p 801,
Washington, D C , American Pharmaceu-
tical Association, 1955
36 National Formulary, 11th ed , p 491,
Washington, D C , Amencan Pharmaceu-
tical Association, 1960
37 Olsen, P C IJ refills overtake new
scnpt business, Drug Topics 106 41, 1962
38 Prescnption Survey Report, Amencan
Druggist /45 7, 1962
39 Report of Committee on Government
Operations, Veterinary Medical Science
and Human Health, p 159, Washington,
D C , U S Government Pnnting Oflice,
1961
40 Ibid.p 171
41 Rising, L W Professional consulting — a
neglected function of pharmacy, Am J
Pbarm. Educ 26 209, 1962
42 Rubin, A Desk Reference and Directory,
p 10, Washington, D C, Amencan Po-
diatry Association, 1962
43 Op cit, p 87
44 Schenng booklet, op cit,p 29
45 Sheps, C G Problems, pressures, and
prospects, J Med Educ 36 3, 1961
46 Siskin, M Senior dental students wnte
Bs, pharmacy students fill them, APP
28 34, 1962
47 Stephenson, H C , and Mittelstaedt, S G *
Vetermary Drug Encyclopedia and Thera-
peutic Index, 9tb Edition, p 7, New York
City, R H Donnelley Corp , 1961
48 Survey by Professional Market Research,
Drug Topics, 106, No 2, p 27, 1962
49 The Homeopathic Pharmacopeia, 6th Re-
vised Edition, p 33, Boston, Amencan In
stJtulc of Homeopathy, 1941
50 Therapeutic Agents for DENTAL Medi-
cine/Surgery, p 18, Bloomfield, N J,
Schenng Corporation, 1961
51 Ibid ,p 18
52 Therapeutic Agents Useful in Dentistry,
p 4, Indianapolis, Eh Lilly and Co , 1961
53 Ibtd.p 11
54 Ibid , p 21
55 Ibtd.p 26
chapter 12
Prescription Accessories
and Related Items
Walter Singer, Ph D.*
The term prescription accessories was
corned in 1949 to categorm: the many items
uhich the pharmacist provides to meet the
needs of the patient who is being cared for
at home * It encompasses a wide range of
devices from which there has been selected
a represcQtaUve sampling for discussion in
this chapter These and related items arc
sometimes altcmauvcly designated as raedici*
nal adjuncts, sick>room supplies, convales*
cent ai^ or surgical supplies
As these names imply, a prescription usu-
ally IS not essential to the legal dispcnsmg of
such devices Ocarly, society has designated
to the pharmacist the pnmc responsibility for
informing the lay person or the presenber
Vihcn there is need for appliances or supi^ics
necessary to ensure correct use of medicines,
to provide desirable correlative care of the
sick individual or to enhance his comfort
Additionally, the pharmacist is expected to
advise micUigcntly m the choice of a suitable
accessory from among the variety of avail-
able competitive products Mhich may seem
indistinguishable to the untramed e)e He
must warn against dangers of misuse as well
as mform about correct use, maintenance and
storage This chapter is onented toward sup-
pl)U)g basic and specialized information
alMUt properties and uses of prescription ac-
cessories so as (o permit the phonnacist to
meet these multiple responsibilities now and
m the future Obviously a suitable intern-
ship under a preceptor knoi^lcdgeablc in this
*Ai%btact Profeuor of Phannac}' aoJ Fbanna
ceuti^al Chenusiry, Univtmiy of California Scboid
of Pharmacy, San Franciwo
area is a desirable complement to the dis-
cussions presented herem The choice of ac-
ccssoncs to be discussed has been governed
by several factors Some devices deserve men-
uon because of their widespread usage, as
shown in Table 86 Most attention is given
to those whose complexity in design or use
leads to opportunity for a professional serv-
ice Others (such as orthopedic appliances)
demand training in fitting or adjusting to the
degree that quite extensive course work at
specialized schools is almost mandatory for
obtaining suHicient information to be truly
useful l^ese are not discussed.
CLINICAL THERMOMETERS
Body temperature is commonly assumed
to remain at so constant a level m health that
a deviation from the limits of the accepted
normal range is regarded by the physician
and the layman as diagnostic of body mal-
function Fallacies in this concept have been
pointed out A satisfactory approxima-
tion of the temperature of the interna] organs
can be made b^ insertion of a suitable ^cr-
roometer mto cither the mouth or the rectum,
these being closed cavities with fairly large
blood vessels Studies^'' of large samples of
norma! individuals have showTi oral tempera-
tures to range from 97 0 to 100 4° F with
98 6* F popularly accepted as average (Fig
129) A diurnal vanation of nearly 2° F
71)6 author wiibes to express hu grautuJe to Mr
Doa HascUon who took the onpinal pictures for all
the figures in thu chapter with the cxcepuoa of
Figures 135, 141, 149, 159 and 165
400
Clinical Thermometers 401
Table 86 Sales of Prescription Accessories in Pharmacies
Accessory
1962 Sales IN
Pharmacies*
Pharmacy % of
Total Sales
Suspensones
$ 1,190,000
92
Medicated plasters
4,100,000
91
Medical atomizers
1,500,000
90
Vaporizers
10,680,000
86
Eyecups, enamelware, hard rubber specialties
1,830,000
82
Flat goods, water bottles etc
10 ,000,000
77
Ice bags, icecaps
880,000
73
Feminine bulb syringes
1,750,000
Infant bulb synnges
4310.000
74
Folding synnges
4.330 000
71
Heating pads
13,000,000
67
Men’s supporter belts
2.440.000
66
Fmt aid supplies
98.560,000
57
Other elastic goods
7,730,000
52
Trusses
3,670,000
49
Heat lamps
2,060,000
40
Fever thermometers
9,760,000
40
Athletic supporters
3,530 000
36
Invalid nags
820,000
34
Abdominal belts
2,320,000
29
Elastic stockings
6,380,000
22
Crutch tips, pads
800,000
19
Colostomy appliances, unnals
18
• Data from Olsen P C 'Vhat customers spent for all products sold in drug stores Drug Topics
107 6, July 15, 1963, Olsen P C Pharmacies up five million dollars m first aid sales Drug Topics
107 40 July 1, 1963 y *C
may occur with minim a m the period of low
activity between 2 and 6AM and with
maxima at active periods in the afternoon “
Rectal temperatures are said to be 1® F
higher than oral, although differences of only
07to09“F are frequently encountered
Values above 99 4° F orally and 100 3® F
Fig 129 An esumate of the ranges in
body temperature found in normal per-
sons From DuBois, E. F Fever and the
Regulation of Body Temperature, Spring
field, IlL^lhomas^ 1948
Heat Stroke
Brain lesions
Fever Therw
F csRitE Disease
AND
Karo Exerdsc
TEMPERATURE
Regulation
SERiousur
lURAIRED
TEMPERATURE
REGULATION
Efficient in
FEBRILE Disease
Health AND \M0RK
J ltMPERATURE
Regulation
Impaired
temperature
Regulation
Lost
Fig 130 Extremes of human body
temperature with an attempt to define the
zones of temperature relation From
DuBois, E. F Fever and the Regulation
of Body Temperature, Spnngfield, 111 ,
Thomas, 1948.
402 Prescnpiton Accessories and Reloted Items
Fio 131 (le/t) Types of clioicot (her
mometcrs A. Security bulb B Basal
thermometer with oailhcad stem C Oral
bulb, flat type stem D Rectal bulb, ceo
Ugrade scale (RighO A model of the
constriction chamber of a elinical ther*
momeier Powdered iron (appeanog
black) IS used to represent the mercury
The central depression or ''air bubble is
made by collapsing the healed wail of the
stem so as to obliterate the center of the
lumen The openings around the depres
sion are about 00006” in diameter in the
clinical thermometer
rcctally arc coosidcrcd fcbnic, with perhaps
5 per cent chance ol cnor m this respect
Feser may have an emoUonal coni{:«ncDt,
but, more frequenUy, elevation of body tem-
perature above normal is caused by an in-
tcctious process inflammation of an area,
bram mjury, dehydration or certam drugs
Temperatures below 96 6" arc considered
subnormal Malnutrition, shock, excessive
perspiration or prolonged exposure to cold
may lead to low body temperatures While
the exact mechanisms by which changed
locls of body temperature arc produced and
maintained are not known, such shifts are
said to be due to “resetting the hypothalmic
thermostat” Physiologic aspects of body
temperature, temperature regulation and fever
have recently been well reviewed” Body
temperatures under dilTcrcot conditions are
illustrated m Figure 130
Characteristics and Manufacture of Ther-
mometers. The expert design of the chnical
or fever thermometer (Fig 131, left), which
permits measurement of temperature with
ease and accuracy, often is not appreciated
by cither the user or the pharmacist The
thermometer, about 4 mches in over-all
length, IS short enough to be supported m the
mouth or the rectum without difliculty and
to be easily carried about or stored, yet its
scale may span as much as 18® F In order
to obtam maximum linear movement of the
mercury with small changes m temperature,
the thermometer bulb is made quite large
while the diameter of the stem capillary is
only about 0 001 to 0 004 inches, approxi-
mately one tenth that of the human hair**
The stem tubing is tnacgular m cross-section,
forming a prism so that the column of mer-
cury 15 magnified os the user looks at it
through the apex VisibiLty is enhanced by
the background fumisbcd by ao opaque strip
of glass fused along the base of the triangle
Smee the scale is not easily seen while the
thermometer is still inserted orally or rec-
tally. It IS necessary to arrange to make the
mercury column remain at its highest point
even after the thermometer is returned to
room temperature This sclf-rcgistermg fea-
ture is provided by a small constricUon cham-
ber (Fig 131, right) formed in the capillary
about meb above the juncture of the stem
and the bulb The heated, expanding mer-
cury must force its way through the two tiny
openings which penetrate the chamber, but,
as shnnking into the bulb starts on cooling,
these thin columns of mercury break at the
constriction, leaving the column level un-
changed m the stem above After the reading
is taken, the mercury may be forced back
down the stem by shaking the thermometer
vigorously
Oral, rectal and security (stubby) bulbs
arc available (Fig 131) The oral bulb is
^lindncal, elongated, and thin-walled for
quick registration The rectal bulb has i
strong, blunt, p>car shape which aids in inser-
tion into the rectum and retention by sphinc-
ter muscles The short sturdy sccunty bulb
represents a compromise intermediate shape
suited to either o^ or rectal use Acceptance
Clinicol Thermometers 403
of this bulb has increased markedly m recent
years as the pharmacist has made known to
the pubhc its advantages of dual use and
resistance to breakage
Climcal thermometers are not machine-
made Glass blowers form each bulb mdi>
vidually and then jom bulbs and stems m one
of the hrst of the many operations mvolved
m producing a fimshed thermometer ®
Exact reproduabihty in size and shape of
bulb is not possible m such handwork, con-
sequently each thermometer is impredictably
unique m the amount of mercury it contains
Each must have its scale detenmned indi-
vidually by calibration Thus, two thermom-
eters, even though identified by the same
catalog number and sold as equivalent, may
have scale lengths and upper and lower limits
which differ Immersion m water baths ther-
mostated to maintam known temperatures
establishes the mercury levels for the scale
limits of a given thermometer “Pointing”
machmes automatically space and draw tn
intermediate scale markings on the wax-
coated stem which can then be etched by
unmersion m hydroSuonc acid Suitable pig-
ments are pamted into the scale marks to
increase visibihty The Fahrenheit scale is
commonly used in this country, but many
manufacturers make at least some of their
styles available optionally with the Centigrade
s^e
“Hard shakers” with too narrow constne-
tions and * retreaters” with too wide apertures
are detected by appropriate tests and are dis-
carded by lehable manufacturers Thennom-
eters are then stored m “seasonmg vaults”
for 4 to 6 months to allow the glass to
achieve molecular stabihty After thu aging
the accuracy of calibration is rechecked m
thermostated tanks before release for distri-
bution Some manufacturers season their
thermometers before etching m the scale
Accelerated agmg by heat treatment is now
practiced also Minim um requirements for
cUnicai thermometers have been dcvcli^d
by cooperative efforts of manufacturers, dis-
tributors and users along with the U S De-
partment of Commerce These are set forth
m Commercial Standard 1-52 (CSI-52) •
* Available from ihe Supennvendent of Docu
menu, U S. PrinUng OfScc. Washington 25, DC,
at a cost of 10 cents.
Fig 132 Accuracy of thermometers m
use to a hospital (From Dimood, E G ,
and Andrews, M H Chmeal thermom-
etersaodunnometers, J A M A 125)
A certification that this standard has been
met or surpassed is found with each ther-
mometer feme may also certify to comph-
ance with addition^ regulations of Massa-
chusetts, Connecucut or Michigan
Accuracy of Thermometers. Since deci-
sions as to therapeutic regimens to follow may
be based on the presence or the absence of
a few tenths of a degree of temperature, ac-
curacy m a clinical thennometer is an obvi-
ous requuement Rough checks of one ther-
mometer against another may permit the
pharmacist or user to detect gross variations,
but precise determmations of accuracy are
possible only m laboratones with special
control equipment
In a large study, 540 thermometers made
by different manufacturers were selected at
random from pharmacies at vanous wide-
spread pomts m this country and compared
by accepted technics with the accuracy limi ts
presenbed by CSl-52, which all were certi-
fied to meeL'^ Almost 18 per cent exceeded
the allowable error For two brands, charac-
terized as “of foreign manufacture” and as
“promotional items,” standards were not met,
m one case, by 28 per cent (of 144 samples)
and, m the other, by 35 per cent (of 62 sam-
ples) While the pharmacist is not equipped
to make tests of this nature, he at least should
mspect visually each brand of thermometer
offered to him so as to reject those of obvi-
ously poor quality m appearance
Qinical ^eimometcrs arc relatively frag-
ile Many are shattered when dropped while
th^ are being bandied or shaken Bulbs are
404
PreKriplion Accessories and Reloted Items
FiO 133 Thermometer case with whirling
altachment
broken by nnsmg them with hot water Less
obvious and more dangerous arc subtle
changes m the constriction chamber, ‘re-
treaters' m which the level of the column
drops before the reading is taken can result
from slight jarring. Decreases in accura^
may dcsclop m improperly aged mstruments
Separations may occur m the mercury col-
umn * Figure 132 presents the results of a
test of acctiracy of 465 thermometers of a
variety of brands and styles which were u
actual use m a large general hospital ** If one
assumes accuracy at end of manufacture,
ngors of usage had evidently seriously dam-
aged many of these thermometers Retreaters,
hard shakers, defective pigmentation and
mercury separation also were found It is
probable that a large proportion of thermom-
eters that arc currently depended on for home
use have been rendered similarly defective
Use and Maintenance of Thermometers.
Many manufacturers supply more or less
complete directions for use and maintcooncc
with each thennometer packaged for indi-
vidual sale Additional mstruclivc leaflets arc
available and helpful The pharmacist roust
be prepared to illustrate and supplement this
information He might proceed along the fol-
lowing hoes, tailoring his approach accord-
ing to the situation
The pharmacut should advise as to the
choice of bulb Many laymen do not know
that there arc dilTcrcnt bulbs, let alone that
one may have advantages of strength or sen-
sitivity over another This is also an oppor-
tunity to warn agamst rectal use of oral bulbs
The thermometer should be removed from
Its ease and inspected in the presence of the
* Tale hold of the bulb cdJ and shale toward
the lop, then reverse and shale toward the bulb
This should mend the break unleu other damage
has been done to the thermometer
purchaser to be sure that it is mtact and that
the bulb IS of the t)pc marked on the outside
of the package Identiflcation and explana-
tion of the constnction chamber (the “air
bubble”) may prevent return of an irate
client with the mistaken claim that he was
given a faulty mstrument Holding the bulb
for a few moments will make the mercury
rise enough to permit a demonstration of how
to read a thermometer This will also illus-
trate why the bulb should not be held when
a readmg is being made The pharmacist
should instruct the client as follows, stand
With back to light, hold the end opposite the
bulb between the thumb and mdex finger of
one hand and support the thermometer with
the other hand, being careful not to touch
the bulb, look down at the apex of the tri-
angle toward the engraved scale and rotate
the thermometer slightly back and forth until
the mercury column appears at maximum
width, locate the top of me column with re-
spect to the scale readmg The pharmacist
must explain the scale markings ^Vbl]e the
major degree lines are easily interpreted, the
fact that each of the four mtcrmediate gradu-
ations represents 0 2'* F is not always clear
to the user If the individual finds it diflicult
to see the mcrcuiy column, the pharmacist
should suggest a style especially modified for
easier reading Thermometers with flat stents,
colored backgrounds m the stem or glass balls
that appear blue only when the column is m
position to be read fdl into this category
The shaking down of the column should
be demonstrated hold the nonbulb end be-
tween thumb and index finger and swmg arm
down ending with a snap of the w-nst as
though shakmg water off the fingers, warn
agamst trying to shake down a thermometer
by jarring the hand against a solid object, as
this may damage the constriction, suggest
shaking down be done over a bed as a pro-
tection in ease the thermometer slips from
the fingers If a client seems apprehensive
^x)Ut this operation, demonstrate a style with
a whirling device m which centrifugal force is
utilized to cany down the mercury (Fig
133)
Other information which the pharmacist
may wish to volunteer is found in recom-
mended procedures for use and mamtenance
of thermometers Temperatures should not
be taken for 20 to 30 minutes after dunking.
Cl n ca! Thermometers 405
eating smoking or exercise smce such ac-
tivities may raise body temperature (or lower
It m the case of cold drinks) Always be sure
the column is down to 97“ F or less before
msertmg the thermometer For oral tempera
tures the bulb (oral or secunty) should be
moistened with cool tap water and placed
under the rear edge of the tongue tind rotated
two or three times The tongue should be
held down and the lips should be closed
gently over the stem Breathmg should be
nasal to avoid entry of air mto the mouth
The mdividual should remam at rest The
readmg should be taken after 3 minutes
The thermometer should be replaced m the
mouth for another mmute then reread This
IS repeated until two consecutive readmgs
agree The thermometer is shaken down then
cleaned and disinfected as described below
For rectal temperatures the bulb (rectal
or secunty) and the lower portion of the
stem should first be lubncated for ease of
insertion In order of preference (for rea
sons of adverse mfiuence on disinfection)
the lubricants to use are a water soluble
jelly,* mmeral oil or petrolatum The ther
mometer is inserted gently and pushed with
a mmimum of force until the 98 6“ F mark
passes the anal openmg About one half of
the stem will now protrude The thermometer
should be left m place for at least 4 minutes
An adult will probably be most comfortable
lying on his side Babies should be held face
down perhaps across the knees and the
thermometer supported between the fingers
throughout the entire period The thermom
eter is removed, wiped with cleansing tissue
With the direction of motion bemg from the
stem down over the bulb end and then read
Rectal thermometers are marked — by cus
tom apparently — to mdicate 98 6“ F as
normal although as previously pomfed
out, normal rectal temperature may be
99 6“ F For sake of clanly, both the actual
temperature as read and the manner of tak
mg the temperature should be reported to
the physician As with oral temperatures,
repeated insertion until two consecutive read-
mgs agree may be advisable Longer insertion
tunes will be needed if the thermometer is
cold or if the patient has poor cuculatioo.
Because of recognized mexacUtudes, axil
* K. Y Jelly Johnson and Johnson New Bnuis*
wck,N J
Fic 134 Records of basal temperature
lary or grom temperatures are taken only
when neither the mouth nor the rectum can
be used An oral or a secunty bulb is used
The axilla is wiped dry, the thermometer
placed m the axilla and the arm is held close
to the body to make as closed a cavity as
possible An enclosed space for the ±er
mometer can be made m the grom by flexmg
the thigh on the abdomen At least 10 mm
utes should elapse before the reading is made
An axillary or a grom temperature is usually
1“ F lower than the oral, so 97 6“ F would
be normal
The Basal Thermometer The basal tern
peralure thermometer is a specialized mstru
raent helpful m estunatmg time of ovulation
Smce It IS probable that fertilization can occur
only wilhm the first 24 hours after release of
the ovum from the Graafian follicle accurate
knowledge of the occurrence of this event
would permit Ummg of mtercourse so as
either to enhance or to decrease the possi
bili^ of conception Ovulauon occurs once
during each normal menstrual cycle approxi
mately 14 days before the next menstrual
penod Basal temperature the lowest tern
peiature reached by the body of a nor mal
healthy person while awake typically passes
through a biphasic cycle over the course of
the menstrual cycle The temperature is
mitially low, a mid-cy cle tbcnnal shift occurs
to a high level, where the temperature re-
mains until It once agam becomes low pre-
406
Preicriplion Accessonet ond Reloled Items
nuQStrually (Fig 134) The temperature
nsc mdicatcs that o^ailatioa has occurred one
or two dajs before or will occur one or two
da)s after or is occurring at the moment of
the temperature nse " T^e temperature nsc
IS said to be related to the presence of pro*
gcslcronc or some combination of proges-
terone and estrogen in the systemic circula-
tion “ In spue of the lack of deSmtude,
which has led some physicians to consider
the method quite limited,** *** others con-
sider It reliable **
An ordmary fever thermometer is not very
satisfactory for mcasurmg the small tempera-
ture rise of about 0 5“ F which is related to
ovulation The basal thermometer (see Fig
3) is easier to read, since its scale, ranging
ody from 96“ F to 100® F , is graduated
to 0 1® F rather than to 0 2® F The bulb
resembles an elongated security type Tem-
perature IS taken either orally or rcctally,
once daily, unmcdiaiely on awakening in the
mommg and before getting out of bed Rather
explicit directions and charts for recording
these daily measurements are provided with
the thermometer Since each woman vanes to
some extent in her ph)sical characteristics,
each must determine her own menstrual
rh)lhffl by keeping this record for 3 or 4
months Coosultauon with a physician is
essential for proper interprctauon of the
chart
Cleaning and Disinfecting Tbcrmomelcis.
The cluucal thermometer should alvva)s be
cleaned and disinfected after use, to mnu-
mizc transfer of pathogens The proper pro-
cedure for doing this has been the subject of
numerous mvcsligations Con-
sideration of these reports leads to the fol-
low mg suggesUons After oral use the ther-
mometer should be wiped thoroughly with
clean cotton w ct with a solution of cqu^ parts
of tmeture of green soap and water * Wiping
should start on the stem and proceed toward
the bulb After a rinsing with cold ruamng
water, the thermometer should be immersed
to at least halfway up the stem for 10 to 15
minutes m a solution of 0 5 to 1 0 per cent
iodine m 70 per cent rubbing alcohol, either
■ In place of water 95 per cent cU))l alcohol has
been recommended^ for admUlurc here but the
itight increase in effectisencss docs not justify the
added expense
ethyl or isopropyl The 70 per cent alco-
hols without added lodmc seem nearly as
cdcctive, so are aqueous solutions of 0 05
and 0 25 per cent iodine m 1 per cent potas-
sium iodide A 0 I per cent tmeture of
bcnzalkomum chlondc has been found to be
eflecUve against usual oral pathogens, while
aqueous 0 1 per cent was noL*®* Neither was
reliable against the tubercle bacillus ***
Certain synthetic phenolic dismfcctants arc
useful m 2 or 3 per cent concentration **‘
Other strengths of alcohols, t e , 50, 95 or
100 per cent ethyl alcohol and 99 per cent
isopropyl, arc reported mcflcctivc as arc
certam lodophors (contaimng 200 ppm avail-
able iodme solubilized with nonionic deter-
gents) After suitable disinfection the ther-
mometer should be nnsed with cold water
and wiped dry with clean cotton or tissue
Some suggest that a similar procedure should
be followed immediately before use as well
as after The thermometer should be stored
in its cose Continued immersion in anu-
septic soluuon IS not recommended, as thu
may damage scale pigments Followmg recta!
use, the thermometer should be wiped with
dry, clean ussuc to remove most of the fecal
matter and the lubricant before rcadmg il
Then the same disinfection procedure can be
followed, smcc rectal pathogens are suscepu-
ble to It *‘* Greasy lubricants such as petro-
latum and mmerid od have been shoivn to
interfere with dismfccuon ***
Thennometer Cases and Acccssoncs. A
hard rubber or a plastic ease resembling a
fountam pen is usually furnished so that the
thermometer may be stored safely The case
may or may not have on external clip for
pocket use Typically, Uicrc is an inner spnng
which gnps the thermometer to keep it from
sinking the sides or folhng out. Some eases
are leakproof so that the thermometer can
be stored in onuscpiic solution, this may be
justified in spite of damage to scale pigments
when there is extreme possibihty of transfer
of infectious organisms as m a senes of house
calk by a phjsiaan Whirling devices arc at-
tached to some eases to help in shaking down
(see Fig. 133) Elaborations in design of
eases may add to the cost of the thermometer
without real gam to the pauenL The pharma-
cist and the user should avoid storing the
thennometer near heat or in sunlighL
Rubber and Plastic Accessories 407
It IS quite possible that the home into
which the cluucal thermometer is bemg taken
may lack any or all of the foUowmg adjuncts
to Its effective use and mamtenance properly
labeled dismfectant solution, cotton balls, tis-
sues, tmcture of green soap and a water-solu-
ble lubncant The phaimaast who is alert to
his responsibilities for service will keep a sup-
ply of these items near his thermometers and
w^ advise of the need for them when it seems
appropnate to do so
Thermometers Broken in Situ. Clmical
thermometers are frequently broken m situ,
especially m the mouths of children This im-
mediately arouses concern, and advice is
often sought from the pharmacist Mehnert**
surveyed the medical literature and com-
mented on his failure to find a sm^e report
other than his own of serious injury related
to breakage of a thermometer m the mouth
In the case cited, the broken bulb (rectal)
had not been recovered after the accident
More than two years later, it was discovered
that the tip bad penetrated the hilum of the
submaxiU^ gland The released mercury
had gravitated into the ^and and also under
the skm of the neck. Investigauon of the
cause of. the pain and the tumorlike appear-
ance of the region led to its discovery Me
tallic mercury is not dissolved appreciably if
at all m the gastromtestinal tract Little ab-
sorption occurs even though the mercury
may become dispersed as very fine droplets
ihrou^oul the mtcslmes ® Lack of toxicity
IS suggested by the once common oral ad-
ministration of as much as one pound of
mercury in the treatment of obstipation *
^Vbea a thermometer is broken m ^e mouth,
primary concern should be directed toward
the recovery of as much of the glass (and the
mercury) as possible and the stoppage of
bleedmg from cuts It is wise to give the white
of egg as an antidote for mercury, thus, per-
haps, errmg on the side of caution Soft bread
to coat swallowed particles of glass to pre-
vent damage to the intestines has been sug-
gested A physician should always be
called. It may take as long as 14 days for all
the mercury to lease the body m fecal mat-
ter * Breakage of thermometers m the rertum
seems less likely to occur and to mvolve
snapping of stems rather than crushing of
bulbs Here the mam problem is one of need
for dextenty and care m removmg the rem-
nants of the thermometer
RUBBER AND PLASTIC
ACCESSORIES
A number of the devices designed to assist
in makmg the sick more comfortable, m the
ungaUng of body cavities and the coUectmg
of body secretions are made largely of rub-
ber because this matenal is soft, tough, im-
permeable, easily formed and elastic — a
umque combmation of properties that only
recently has been achieved m the synthesized
elastomers which can match it m most of
these properties The fascmating story of the
mtroduction of rubber mto European civili-
zation and Its subsequent growth to a posi-
tion of top economic importance is recounted
m detail m readily available encyclopedias
Properties op Rubber
Natural rubber, an isoprene polymer
(C»Hg)B, IS obtained as an elastic solid from
latex (sap) of the rubber tree {Hevea
braziUensis) or from similar sources Latex*
1 $ a milky, sticky fiuid contaming about 35
per cent of raw rubber (caoutchouc) as a
colloidal aqueous suspension of globules
Latex concentrated to 60 per cent rubber
and preserved with ammonia against spon
taneous coagulation is itself commercially
available Alternatively, at the rubber planta-
tion a weak organic acid (fonmc or acetic)
IS added to latex to cause the rubbes gjobules
to come together to form a coagulum The
coagulum may be washed and rolled into
thm sheets which are dned m air to form a
yellow white crepe rubber, sodium bisulfite
IS added dunng the processing to prevent
browmmg due to oxidation Sometimes the
washed coagulum is rolled to heavy sheets
which are dned m hot smoke ansmg from
bummg wood The smoke acts as a preserva-
tive and also turns the rubber brown Latex,
crepe rubber and smoked sheet seem to be
ranked m this order of excellence os startmg
matenals for rubber health goods
Raw rubber has limited usefulness, since
It soItcQs and becomes sticky at summer tem-
peratures while It IS bnttle at low tempera-
*An aqueous emulsion of synthetic rubber or of
plastic is also called a latex.
408
Prescnphon Accettonet ond Related Item*
turcs. Also, It ts dissolved by conunoo organic
liquids including gasoline Cements, surgical
adhesive tape, insulating tape and crepe
soling arc made from naturd rubber The
prmcipal treatment of rubber to improve its
properties IS vulcanization, ic , heating with
sulfur Changes m properties with tempera*
turc ore lessened and resistance to solvents
is mcrcascd Soft rubber contains 2 to 10
parts of sulfur, hard rubber 20 to 50 per cent
Accelerators such us thiuram sulfides, di-
phcnylguamdinc or other agents arc added
to speed up vulcanization Matcnals such as
zinc oxide, carixin black and clays arc fillers
added to modify stiffness, strength and re-
sistance to abrasion and chemicals Anti-
oxidants — for example, phenyl-alpha or
phcn)l beta naphthylamine — are needed to
prevent deterioration Solid pigments includ-
ing lithoponc and titanium dioxide, or solu-
ble d)cs of the phihalocyaninc and the azo
families arc used to impart color Proper
choice of additives and suitable tailonng of
the rubber for intended use are hidden as-
pects of quality which arc difilcult to evaluate
m rubber health goods
Plastics and synthetic rubbers have already
replaced natural rubber m many uscs'^ and
are beginning to do so in the rubber health
goods industry The newly developed stereo-
regulated elastomers such as polybuladicnc
and CIS polyisoprcnc may well be used when
they become available in sufficient quantity
Excellent brief reviews of the nature and the
properties of these matenab have been pub-
lished “ “* Neoprene, which is polymerized
l-chlosobutaditne 1 ,1 , vs used because vl le-
sists oil, sunlight and ozone dcicnoraiioo
Plastics which make up part or oU of a num-
ber of appliances ore polyvm)! chlondc,
pol)st>rcne, polyamide (N)lon) and poly-
cth)lcnc Manufacturers use coined names
for these plastics often without otherwise
idcntif)ing them m the dcscnptions of their
products
Tub MASurACTURE or Rudder Goods
The major steps’^ in the manufacture of
rubber goods arc (1) the kneadmg of the
warmed raw materials m specialized rouccs
until homogeneous, (2) the forming of the
desired shape and (3) the cunng, usually by
hcaung. for puqiosc of desenpuon it is con-
venient to organize these items into groups
lUKTOrding to the method of forming the
shape, I e , by molding, flattening into sheets
or immersion of forms (mandrels) into fluid
dispersions This plan is deviated from (as
m the ease of elastic support Hems) where
groupmg according to a common therapeutic
usage seems more fnutful Also where apro-
pos, nonrubber appliances arc described
SttEETivG Goods
Sheeting may be made by forcing rubber
mixtures to pass between heated rollers (cal-
enders) Hospital film, a thin ( 004 to OOS
mehes) transparent sheeting made by calcn-
denng, can be used to make pillow covers
and the like, since it is readily cut to size
and the cut ends con be scaled together with
a hot iron Dam is a similarly formed but
thicker (approximately 015 inch) sheeting
Since It IS used as an occlusive covering over
wound dressings, dam is available in stand-
ardized widths and lengths with attached tic
tapes
Shceimg may also have a fabric base The
fabnc, usually cotton, may be coated by the
Macintosh process m which a naphtha solu-
tion of rubber is applied to the surface A
thinner sheeting known as rubberized vode ts
made by polymenzing neoprene within tlic
meshes of the cloth These supported and
therefore, stronger sheetings arc used to make
protective garments and protective coverings
for mattresses
Plastics, cspcaally polyvinyl chlondcs
(Koroscal, Zonas), arc used as sheeting ma-
tesvals bceavive they have less wdoi and greater
resistance to teanng than rubber They also
seem cooler to he on Unsupported sheeting
of both film and dam thicknesses as well as
the fabnc type arc available m rolls 36 to 54
inches wide and 25 or 50 yards long
Rubber sheeting can be laundered with
warm water and mild soap It con be dis-
infected and odors removed with saponated
cresot solution or formaldehyde solution
Autoclaving for not more than 20 minutes or
immersion in boiling water for not more than
IS ore also safe, especially if followed by a
12 hour penod of nonuse to allow loss of
absorbed water Sheeting should not be folded
sharply or wadded It * fatigues” or loses its
strength along creases formed from repeated
Rubber and Plastic Accessories
409
Fia 135 {Left) Fountain syringe and water bottle Slip type pipes are shown, the
larger is a vaginal tip the smaller is an adult rectal tip The shut off on the tubing is the
spnng type {Right) Combination synnge-water bottle Screw type pipes and a lever shut
off are shown *I^e water bottle stopple is lying at the left and Die hollow synnge stopper
at the right of the neck.
folding, so It IS recommended that sheeting
be rolled rather than folded for storage
Molded Goods
Water Bottles and Synnges. Water bottles,
fountam syringes and combination synnge-
water botUes are flat bags, essentially rec-
tangular in shape (Fig 135), all of which
are molded in about the same way Two
pieces are cut from a sheet of heavy com-
pounded rubber and placed against the inner
faces of a two piece mold The mold is closed
tightly and compressed air is admitted to
keep the inner surfaces of the bag from stick-
ing together while the mold is bemg heated to
fuse edges and to cure the rubber The
seam is usually covered and reinforced by
cementing or fusing a thin stnp of sheeting
over It The neck of a water bottle or a com-
bination syringe has a threaded metal (usu-
ally brass) collar The collar may be molded
m as a part of the ongmol operation or it
may be mcorporated separately mto a bard
rubber ring which is cemented mto the neck
later A hard rubber or a plastic stopple of
standardized shape and thread is provided to
close the bag The combinatioa syringe has
m addition a specialized hollow stopper ter-
minating m a short pipe to which tubmg can
be attained. The neck of the fountam synngc
cannot be closed of! and instead may be
widened or funnel shaped to make it easier
to pour water mto iL The base of the foun-
tain syringe has a bard rubber or plastic
outlet to which tubing may be attached Ac-
cessones to the fountam and the combmation
syringe mclude tubmg, a shut-oS and tips or
pipes (Fig 135)
Most companies make three or four grades
of quality m these articles Cheaper botdes
may be thmner walled and contain lower
grade rubber with large amounts of mmeral
filler or of reclaimed rubber, making them
less clastic and shorter lived Wei^t is not
neccssaniy an mdication of quality Tubmg
IS usually about 9/32 of an mch in mtemal
diameter and S feet or slightly less m length
but varies significantly m quality Less ex-
pensive syrmges have a simple spnng or snap
shutoff to stop Sow through the tubmg, while
better ones have a more efficient and more
easily operated lever ^"pe Either two or
three tips are furnished, there is usually a
vagmal imgator and an adult rectal and
sometimes an infant rectal These may be
hard rubber, vinyl or nylon Slip types which
slide into the tubmg are cheaper and mote
likely to allow leakage than the screw-on
type The packagmg may become progres-
sively more elaborate as the cost of the item
410 Prescription Accessories ond Related Items
increases A guarantee against dcfccuvc work-
manship or material is gisen for penods of
time which progress from 1 or 2 jears up
to 5 ^cars for the more expensive bottles and
s)nngcs While the pharmacist can readily
point out quality diiTcrcnccs to a prospective
user when he is comparing items made by
one company, it is more difficult to make a
logical choice between equally pneed items
made by competitive suppliers It is probable
that significant differences do not exist
jya:er bottles ordinarily are used as a
means of appl)uig dry heat to a limited body
area m order to induce vasodilation and
leukocytosis, relax muscles and connective
tissue or hasten suppuration Reflex relief
of congestion m uiicmal organs may result
Hot moist applications arc more cticcuvc for
promoting drainage from wounds and skin
lesions Heal is contraindicated^* when vaso-
dilation will mcreasc pain os in a swollen
sprained anUe or an infected tooth Heat
should not be applied when it would be dan-
gerous to hasten a suppurative process (os
m appendicitis}
Because the water bottle seems to be such
a simple device, the user may be unaware
that there is a correct way to use it for maxi-
mum benefit with minimum danger The
water should be heated to 120® to 130® F
for ao adult or to 110® to 120® F for a
child or an unconscious or an elderly person
The healed water should be placed in a
pitcher and adjusted to temperature with a
suitable thermometer before pouring it mto
the water bottle The pharmacist may find it
difficult to justify purchase of a thermometer
along with a w-atcr bottle for short term use
As an exjKdicnt he may suggest testing the
water by hand, it should be uncomfortably
hot but not unbearably so Hot water from
the tap may be over 140® F and should not
be run directly into the bag The bottle should
first be filled With hot water, stoppered and
tested for leaks by applying pressure The
warmed bag should be emptied and then
filled only' to one half or three quarters of
Its capaaty A completely filled bag is un-
comfortably heavy against the patient and,
also. IS unable to conform to body contours
Repeatedly filling the bottle to bulging with
hot water will stretch it out of shape and
hasten detenorauon of the rubber Next, the
bottle should be placed on its side with the
neck held up to prevent spilling while pres-
sure of the hand along the flat surface
squeezes the water up mto the neck of the
bottle, thus cxpctlmg the air and making the
bottle more flexible The stopple should be
screwed in tightly and the bag turned upside
down to be sure there is no leak at the neck
The outside of the bag should be dried and
It should be wrapped m a towel or enclosed
in a fitted cloth cover before placing it against
the patient This will decrease possibility of
burning the skin and will also sene to ab-
sorb perspiration Hot water bottles require
refilimg every 2 to 4 hours After use the
bottle should be drained completely and
hung upside down by its tab until dry Air
should be blown m to keep the inside sur-
faces apart, the stopple mserted and the bag
stored in its box m a cool place to protect it
from heat, ozone and sunlight, which de-
tenorate rubber
The foiiiiiam syringe is used to supply
water or special solutions for enemas or for
vagmal imgations (douches) An enema is
the lojecuoo of fluid into the rectum and the
colon so as to cause contraction of the colon
and the impulse to defecate'®^ as a response
either to the pressure sensations created or
to irritants contained m the fluid Enemas arc
givbo to relieve constipation (either real or
fancied), to cleanse the bowel before surgery
or before barium visualization, to help escape
of gas from the colon or to inject fluids to
be retained for local or systemic effects
Liquids used include tap water, normal saline,
1 to 2 per cent sodium bicarbonate or weak
soap solutions These may be warmed to
about 100® F, but they should not be hot
About 1 quart of liquid is put mto the bag
for a clcansmg cncmx The hard rubber rec-
tal Up is well lubricated, preferably with a
water soluble jelly, smee petrolatum has an
adverse efiert on rubber The newer plosuc
Ups arc said to have smooth surfaces slick
enough to be mserted easily without prior
lubrication Air is climmatcJ from the tubing
by allowing a small amount of soluuon to
run out into a contamcr The inflexible hard
Up must be inserted into the rectum very care-
fully and with due allowance for the inevi-
table mvoluntaiy protccuve spasm of the
rectal sphmeter muscles which will occur as
Rubber and Plastic Accessories 41 1
the insertion starts The adult rectum is
about S or 6 inches long so the tip should
not be inserted more than 4 mches, I or 2
inches is usual for insertion for infants The
syringe is hung or held up so that the top
level of the fluid is 18 to 24 inches above the
patient’s buttocks The tube shut-off is re-
leased to allow fluid to flow slowly The fluid
should travel the entire length of the colon
(about 5 feet), reaching the ileocecal valve
m 5 to 8 minutes Smce the capacity of
the average adult colon is about 750 cc , be-
tween 500 and 1,000 cc of enema fluid are
needed to produce the pressure necessary to
stimulate penstalsis The patient should try
to retam the fluid for 5 or 10 minutes so that
the feces may be softened If the bag is held
too high the outflow will be too rapid and a
small amount of fluid will imtiate the defeca
tion reflex without gettmg high enough to
cleanse the colon or to soften the feces
After use, the rectal tip should be wiped
with clean tissue, washed and dismfected by
immersion in saponated cresol solution or
one of the synthetic phenol solutions* for not
more than 15 mmutes followed by a 1 mmute
immersion in rubbmg alcohol (70 per cent),
and then dned The bag and the tube should
be nosed out and hung up to dry before
being returned to the box for storage The
shut-off should be removed from the tube,
smce kinked rubber detenorates rapidly
Disposable enema units are popular for
home use because of convemence, safety and
effectiveness The Fleetf enema unit (Fig
136) is a 135 ml compressible polyetbyleoe
bottle with an aqueous solution of 16 per
cent of sodium biphospbate and 6 per cent
of sodium phosphate It has a short pie-
iubneated tube and an internal rubber dia-
phragm to prevent too rapid admimstration
A similar oil retention disposable umt is also
available Travad^ (Fig 136) is a dispos-
able enema umt made up of a polyvmyl chlo-
nde bag with an 18 mch length of flexible
tubing which allows self administration m
* Two per ceot Amph}! or 0 S}1 (Lcba & Fmk.
Toledo Ohio) are cUccuve
t C. B Fleet Company Inc. Lynchburg, Vir
gima.
t Flint, Eaton & Company, Morton Grove
lllinnK ,
T
Fig 136 Disposable enema units
the sittmg position The fluid is a 135 ml
aqueous solution of sodium dibydrogen phos-
phate (12%) and sodium ntrate (10%)
It may be heated by placmg the bag m warm
water The entire umt will withstand botUng
or steam sterilization
The pharmacist should know the purpose
for which a syringe is to be used so that he
can advise as to its use and prevent misuse
For example, enemas, like cathartics, are
contramdjcated m the presence of undiag-
nosed abdo min al pain and should not be
employed regularly as a substitute for normal
physiologic control of defecation
Vagina] imgaiion is commonly done for
cleansing purposes The vagmal mucous
membrane lining is folded and covered with
protective secretions and it is not easy to
clean the canal Solutions containmg ^nc
acid, borax, alum, vmegar, lactic acid, sur-
factants, phenols or similar mildly antiseptic
or acidic matenals®* are used, generally m
amounts of 2,000 cc or more The vagmal
tip has a ribbed, somewhat bulbous end with
a number of small openmgs around the bulb
so as to give a spray effect The user should
be lymg on her back m the bathtub with the
douche bag suspended not more than 3 feet
above the body level The synnge tip is m-
serted gently downward and backward until
a resistance is felt The lips of the vagma are
pressed about the nozzle to prevent the fluid
from escaping and the fluid allowed to run
until a feeling of fullness mdicates the vagma
IS filled to capacity After a moment, the lips
of the vagma ore released to allow the solu-
tion to run out This process is repeated until
the solution is used up After use the equip-
412 Prescnption Accessories and Related Items
mcnt should be nnscd, dried and stored as
desenbed for Uic water bottle
The folding or travel st)le of fountam
s)Tingc (Fig 137) IS increasingly m demand
because it can be Gtted compactly into a
small space for easy storage and carrying
The syringe u narrower than usual m shape
but has an inverted pleat along each edge so
that addition of fluid to the bag everts the
side panels to give an overfall capaaty of
2 quarts or more The best grade of rubber
(te, latex) IS used for maximum extensi'
bdity and strength To appeal to the femmme
patron these arc made m a variety of colors
and have attractive carrying cases
lee bags or caps may be made m molds in
much the same fashion as water bottles, but
a variety of shapes are made to permit appli
cation of dry cold to spcciGc parts of the
body (Fig 138) Tlic throat and spinal icc
bag IS long and narrow and may have uc tabs
at each end so that it can be fastened in place
around the throat or the abdomen Some
throat or tonsillectomy collars arc perma-
nently formed into a ring by metal spnngs
incoiporated along the perimeter Molded icc*
caps arc flat, somewhat circular m outline
and have a large central openmg for the icc
The English type icecap is not molded, but
ts made of cloth cubbenzed by the Afacintosh
process A thin layer of rubber is deposited
from a solution placed bctvvccn two thicL-
ncsses of cotton cloth Then an ornamental
(usually chccVcrcd) doth matcnal is
mented to one surface to make a nonsweaung
Fio 138 Icc bags [Leji, lop) Throat
and spinal bag (Ltfl center) Ice cap
{Left bottom) Curved tonsillectomy col
lar iRigbt) One of the two English type
caps has been flaltencd as it would be
when used
exterior while the other surface is made mois-
tureproof by painting on a rubber solution A
cylinder of this layered cloth is cemented to
a circular bottom and fastened into a metal
collar to form a multiplcatcd bag which will
stand erect or which can be flattened by tele*
scoping the top into the bag (Fig 138)
Bags are made to be 6, 9 or 11 inches m
diameter when flattened
Icc should be broken up into small pieces,
roughly walnut-size, and nnsed with water
to melt off sharp edges before being put m
the bag The bag is filled one half to two
thirds full, the air pressed out and the stopper
screwed in The outside should be dried and
the bag tested for leaks English icecaps do
not require covering, but other styles do
The ICC needs replenishing every 2 to 4 hours
After use the bag should be washed, dried
and stored in a cool place
The pnmary clTccts''^ of the moderate dry
cold of the ICC bag application include con-
traction of superficial blood vessels, pale cool
skin, decrease m local perspiration, goose-
flesh and, perhaps, shivering Secondarily the
superficial vessels dilate, skin becomes
warm and red, perspiration increases Reflex
ciTccis, such as the stopping of nosebleeds by
cold application to the back of the neck, may
be elicited. Therapeutic uses of dry cold seem
quite limited,'* Contraction of blood vessels
may reduce circulating fluids in an area and
Rubber and Plashc Accessories 413
Fio 139 Invalid cushions {Left) A
polyethylene foam type An in
Sated nng
relieve pam caused by pressure Control of
hemonhage, checking of mflammauon and
prevention of suppuration may be achieved **
ReSex vasoconstriction of blood vessels in
internal organs may occur Moist cold is
more effective than diy m most of these re-
spects Circulatory stasis and injured tissue
are contramdications to apphcation of cold
Invalid Cushions. Persons who spend much
of their tune m a sitting or a recumbent posi
bon are more comfortable when their weight
IS distributed broadly and supported on air
entrapped in rubber cushions One type of
invalid cushion (Fig 139) is molded mto an
inffatable rmg Air is blown m through a
simple type of air valve Clients should be
cautioned that the cushion is hard and tm-
comfortable if too full of air The correct
dimensions must be chosen so as to afford
ptopet support of the pawed tuberosiUes of
the ischium upon which the weight of the
sitlmg person rests ** Weight should be borne
along the edge of the central bole If the
diameter of ^e openmg is too small, the
pelvic bones are forced apart, if it is loo
large, they are squeezed together Since, m
an adult, these bones are normally 4 to 6
mcbes apart, the 14 mch or 16 mch nng is
usually satisfactory The cushion should be
mSatcd and sat on to test for leaks and for
size Circular cushions may become warm
and uncomfortable as radiation from the
body raises the temperature of the au in the
center opening A horseshoe shaped cushion
which permits air circulation and, also, some
adjustment of diameters is available but is
quite expensive Vinyl nngs are now being
FiO 140 Rubber urinal for male
{Top) The lop bas a cloth suspensory
ihe cap shown near the tip can be
screwed on Ibe dram closure to convert
the top mto a dnp unnal The elon
gated bag is screwed on the dram closure
m usual usage {Bottom) Urmal with
tubing connecung top and bag The use
of the tubmg is optional as the top and
the bag may be screwed together directly
The top of this urmal is made of rubber
marketed Small oval mffatable rubber cush
ions, 8 by 10 inches, are designed for place
meat under ears, elbows or heels of bed
nddeo patients with the mtent of preventmg
development of ulcers which frequently re-
sult at these points where bony prommences
may be pressed against the flesh
Cushions m which au* is held os a foam
within multiple rubber cells are now com
petitive in pnee with inflatable nngs and
offer the advantage of mcreased softness and
greater flexibility in design Foams may be
made m several ways Latex can be whipped
m frothmg umts until a foam is produced
This IS poured mto molds, congealed and
wet vulcanized under conditions which pre-
vent evaporation of the water contained m
416 Prescription Accessories and Reloted Items
FiO 141 Diagrams of t)picai eoteros
tomies {Top le/i) The sigmoid aod the
rectum arc removed in a i}pica] colos
torn) {Top right) Iq a typical ileostomy
the colon and a segment of the distal
ileum arc removed {Dotioni left and
right) The colostomy opening is made by
pulling the colon through the abdominid
wall usually in the lower left abdominal
quadrant as shown The ileostomy stoma
IS generally formed in the lower nght
quadrant using the end of the cut ileum
(FromScidc D RN2J 37 1960)
can be left in place for 4 or S days It is re-
moved by lifting one edge and peeling gently
from the skin
During the recovery period after surgery
or during times of intestinal disorders with
attendant diarrhea the patient wdl need to
wear a bag to catch the citcrctions A dis-
posable plastic bag, 6 x S inches, con be at-
tached with a rubber band over the flange
of the C ring in place of the rubber cover
The bag IS di^arucd as necessary Units uti-
lizing a soft rubber sponge against the body
and no cement, and all rubber models, some
with inflatable cushions, arc also available
A number of patients are unable to master
natural control of defecation after colostomy
A survey of some 92 colostomy patients***
showed that 80 per cent bad to cleanse the
colon rcgubrly by imgaiions (enemas ) , com-
monly once daily, usually m the morning An
irrigating appliance is shown m Figure 142
The patient sits on or near the commode m
the bathroom Two or three pmts of warm
tap water (105“ F ) arc put into the assem-
bled fountain syrmgc The catheter (26F) •
is attached to the tube by the tubing connec-
tor and threaded through the bole m the
antisplash cup The distal 3 or 4 inches of
the catheter arc lubncatcd with a water solu-
ble )cUy or With petrolatum The bag should
be hung so that the water level is about 18
inches above tlie colostomy opening when
the user is seated The plastic drain sleeve is
attached at its side openmg to the large rub-
ber nng, then the flat surface of the nng is
held against the body by a belt The open
end of the sleeve is suspended m the com-
mode bowl The water is allowed to run to
expel air from the tube and to contmuc to
flow slowly while the catheter is gently m-
serted to a depth of 2 to 4 mehes The anti-
splash cup 1 $ held against the body to prevent
escape of fluid while the rate of flow is con-
trolled as necessary by pinching the catheter
Ruid containing feem matter is allowed to
pass out of the opemng of! and on during
the imgabon Inasmuch as drainage may con-
tmue for 40 to 60 minutes after imgauon,
the sleeve may be folded double and damped
to make a bag so that the user can move
about After use the componeots of the im
gallon appliance should l:^ washed with de-
tergent, rinsed and allowed to dry A some
what different imgaiion procedure that is
claimed to prevent spillage for 48 hours has
been described
The ileostomy patient has additional prob-
lems because he has a constant and uncon
troUable dnunage of fluid Consequently, he
must wear a permanent appliance cemented
to the skin, usually with a disk rimmed open-
mg at one Side of a flat rubber pouch placed
over the Stoma There is a slccvehkc con-
tinuation open at the bottom end to permit
the emptying of accumulated fluids This is
folded back on itself and damped to make a
dosed container An attached waistbcU pro-
vides additional support Often, a dean bag
IS attached each day, the soiled one being
washed m warm soapy water, rinsed and
dned Vinegar m the wash water is said to
* See Table 68, p. 420, for catheter sizes
Rubber and Plashc Accessories
417
FiQ 142 A colostomy apparatus and irrigation set {Top leji to right) Tht dora^ the C
nog and a folding type fountain syringe The tubing has a lever type shut>oS and is attached
to a one-eyed ca^eter which is inserted into the top of the plastic dram sleeve and through
the opening in the rubber nng by which the sleeve is fastened over the stoma About 4
inches of the catheter has been pushed through the antisplash cup See text for further
descnption
help to deodorize the rubber but eventually
accumulated malodors force the discardmg
of the bag
A questionnaire survey of over 400 pa
Uents with ileostomies”* found that 35 per
cent of the respondents had suffered skin
trouble Many of them reported irritation
m a small circular area of unprotected skin
between the inner nm of the appliance disk
and the iliac stump The stump may not be
enclosed closely by the relatively inflexible
rubber nm since there must be room for
passage of solid objects m the stool The
duration of contact with ileostomy dmmage
and the amount of proteolytic engine ac
tivity m the fluid detemune the degree of
imtation Imtation may result from fluid
seepage beneath a loosened disk Also, the
skin ^neath the disk may be unable to tol
erate cements and solvents commonly used,
reactions appear due to primary imtants
rather than to allergens Trauma from friction
develops as the appliance rubs against adja
cent areas of the body Suggestions mcluded
cementmg to the body a soft sponge rubber
pad which fits closely around the stump and
serves as a base to which the nm of the
pouch could adhere Replacement of poorly
fitted appliances was necessary Karaya gum
was reported to give the most relief of im
tation of all the omtments pastes and pow
deis that were tned • Zinc oxide ointment
or Alummum Paste USP are sometimes
recommended,^*^
In the enterostomy patient the pharmacist
*Spniikle karaya gum Ighlly over the alTected
$ te Allow to fonn sticky paste with scrum present
or add a small amount ot waler if necessary Form
a similar sticky pasle on appliance disk. Place the
disk over the treated skin area. Thu w II adhere
and protect for about 24 hours Somewhat longer
adherence can be obtained by allowing the karaya
gum to become firm on the sbn and then using
nibber cement to glue the appliance on thu pro
tective layer
418 Prescription Accessories and Related Items
FlO 143 Bulb $}ruigcs {Top Ith)
Feminine bulb synnge unh rciracted
pipe {Top right) Feminine bulb synoce
nonrctraciable pipe (Center U/i to right)
Infant rectal synnge ear synnge breast
pump nasal aspirator (Bottom) Ascpio
synnge uith soft rubber tip
has a client who faces severe psychological
roblcms in adjusting to drastic changes in
is way of life Fear of being consider^ dif
ferent or rcpulsnc seems to be common. To
help themselves to adjust to their dtsabihty»
people With enterostomies hate formed clubs
m a number of localities One that is national
m scope IS a mutual aid organization of i]cos>
tomists named QT, Inc after surgical words
Q and T at Mt. Smai Hospital, Newr York,
where it was organized.*”
Bulb syringes arc used to force fluids into
body casiUes such as the car, the rectum or
the \3gina and to remose fluids from others
— the nose for example SyTinges of this type
consist of a hollow bail like part, the bidb
and a holtow tij\whichlnay be either a pro-
longation of the bulb Itself or a lube of dif-
ferent composition inserted mto or otherwise
jomed to the bulb ^Cotnprcssmg the bulb
expels the oir so that fluid can be sucked up
when pressure on the bulb is released and
then forced out agam on rccomprcsston
Bulbs arc made by vulcanizmg rubber or
plastic in molds while inflating the wanned
mixture either with air or with nitrogen gen-
erated by the action of heat on a pelleted
mixture of sodium nitntc and ammomum
chlonde
Bulb syringes are named according to the
part of the body on which they arc used
However, the so-called car synnge is quite
adaptable to procedures other than imga-
iion of the car It is a one piece unit with a
relatively long soft, flexible nozzle tapered
to a small opening (Fig 143} (Capacities
range from 1 to 3 ounces Irrigation of the
external canal of the ear is usually done for
simple cleansing or to wash out impacted
car wax (cerumen) which has hrst been
softened by a few drops of hy drogen peroxide
solution, glyccnn or olive oil ““ A mixture
of sodium bicarbonate (1 6 Gm ), glycerin
(4 cc ) and water (q s to 30 ml ) is said
to soften wax eflccuvcly^* Solutions of sur-
factants are marketed for this purpose,” but
there have been reports of irritation from
liieir use Isotonic saline, 1 to 2 per cent
sodium bicarbonate and tap water warmed to
about 105° F arc among the fluids used for
irngation
In an adult the ear canal runs upward and
forward then downward and forward to the
eardrum’* The pinna should be lifted up-
ward and backward to straighten the canal
while the stream of Quid is directed with low
pressure against the back wall of the canal In
an mfant the eardrum is m an oblique posi
liOQ and covers part of the floor of the caaal,
m order to make the whole canal accessible to
the fluid It IS necessary to draw the auncle
downward and backward ’* Pressure on the
bulb should be gentle and steady, smcc too
much force can be damaging The up should
be held so as not to block the canal in order
to allow return flow into a catch bosm The
amount of fluid to be used is judged by the
clanty of the return flow and the appearance
of the surface of the canal Finally, the canal
should be dned with pledgets of cotton
Unless ordered by a physician, irrigation of
the car is contraindicated when mfccuon is
present or when the eardrum is perforated
Since air bubbles forced into the cor may
produce loud sounds and discomfort, the
Rubber and Plastic Accessories 419
bulb should he filled completely with fluid at
the start In general, this may be done readily,
m the foUowmg way Compress the bulb
and suck up hquid Point the nozzle upward
and squeeze until liquid starts to come out,
then without releasmg pressure put the tip
back mto liquid again Now release pressure
and the bulb will fill completely
Rectal synnges are characterized by the
long and narrow hard rubber or vmyl pipes
which are shpped mto the tip of the bulb
(Fig 143) The infant size has a bulb ca-
pacity langmg from 1 to 4 ounces and a pipe
about 2 mches long, the bulb m the adult
size holds from 5 to 8 ounces and the pipe
IS about 2Vi mches long These are used to
introduce fluids to stimulate defecation, espe-
cially m infants, adults seem to prefer to use
the fountain syrmge for themselves Con-
stipation IS seldom a real problem m chil-
dren Most often it is a diagnosis made by
overworncd parents who have been condi-
tioned to beheve that a dafly bowel move-
ment IS a necessity Pediatnaans consider it
wrong physically and psychologically for a
parent to get mto the habit of giving a child
regular enemas They should be used only
on speaal occasions with the advice of a
physician Authorities** *** *** differ m pro
cedures to follow as well as m the types and
amounts of fluid to use Change of diet is
advocated as a more fundamental approach
to overcoming constipation.***
After use, the syrmge should be wiped
clean of lubricant and fecal matter and
thoroughly washed with soap and water It
may be disinfected by contact with a 2 per
cent soluuon of a synthetic phenol for not
ttmie than IS minutes followed by thorough
nnsmg with water * It should be stored with
the usual precautions for preservation of
rubber
Feminine bulb syringes arc used for
vaginal douches Bulb capacities range from
8 ounces to 10 ounces or more The attached
pipe IS relatively large — about V4 inch m
outside diameter and 5 to 6 mches long It
may be made of inflexible hard rubber or
vmyl. It may be cither straight or sh^tly
curved Less commonly, the pipe is flei^le
The Up has mulupic openings or a removable
perforated screw cap to give a spraying
acuon A heavy soft rubber shield is fitted
around and movable along the pipe There
may be a closure cap for the pipe
bi use, the syrmge is filled completely with
one of the usual douche soluUons, and the
tube 1 $ inserted so that its Up approaches the
inner end of the vagmal canal (4 to 5
mches) Shallower insertion is advised if
vagmal surfaces are inflamed The shield
should be adjusted to fit firmly against the
vagmal entrance The bulb should be
squeezed very gendy to force out its contents
Fluid will be retamed in the vagma as long
as the bulb is kept compressed After the
desired period of apphcation the pipe is
drawn partly out through the shield without
allowmg leakage, the compression slowly re-
leased and the fluid withdrawn mto the bulb
The fluid can then be discarded and the im-
gation repeated as desired The syrmge
should be washed thoroughly with soap and
water and may be dismfected by general pro-
cedures already described It should be hung
nozzle end down to dram and then properly
stored when dry
The feminine bulb syrmge has some ad-
vantage over the fountam syrmge m con-
vemence of use and compactness In fact,
some are made so that the pipe may be re-
tracted mto the bulb for storage m a smaller
space (Fig 143) However, because of the
possibihty that a too forceful outflow will be
generated by excessive pressure on the bulb,
gynecologists generally do not recommend
Its use
The same wammgmay be advanced to dis-
courage the use of the family bulb (valve
syringe) This is a rubber bulb with two
valved openmgs, each attached to a flexible
rubber tube One tube is dipped mto the
imgauon flmd and the other, fitted with a
rectal or a vagmal tip, is mserted mto the
cavity to be irrigated. The valves allow fluid
Sow in one direction only, so alternate con-
stnction and release pumps fluid out of the
reservoir through the bulb and mto the body
cavity There is obviously danger of excessive
force bemg used with this apparatus
The infant nasal aspirator (Fig. 143) is a
1-ouncc to 3-ounce bulb with a 5iort acom-
shaped tip made of glass or clear plastic
It IS used to suck mucus out of the nasal
cavity if It has become so congested that the
infant has difficulty breathmg This pro-
420
Pretcriplion Accessories and Related Items
Table 88 Catheter, Rectal and Colon Tube Sizes
French
10
13
14
16
18
20
22
24
26
28
30
32
34
7
8
10
11
12
14
IS
16
17
19
20
31
22
English
4
5
6
7
9
11
12
14
15
17
18
20
21
0 D (inches)
13
15
18
20
23
26
29
31
33
35
37
40
43
endure js iomchmes recommended as prefer*
able to admmisiraiion of nose drops or as
desirable immediately prior to mstiUation of
such drops The bulb is compressed, then
the tip IS inserted in the nostril i^hite gradual
release of pressure gently sucks out the
mucus This may be repeated 2 or 3 times
Viiih each nostril An car synngc is also use-
ful for the same purpose The Birmingham
style nasal douche is not adsocated for wash-
mg out the mucus, smcc the dow-nward tilt
of the nasal passages necessary for its action
may cause (low of fluid into Eustachian
tubes and the can After use the aspirator
should be washed, disinfected and stored as
usual for rubber goods
Breast pumps (Fig 143) have a I-ounce
to 2Vi-ouocc bulb into which is mserted a
ihtck'Wallcd hom-shapcd glass or plastic
shield about 3 inches long, the open end of
which doles out to a circle with o 2-ioch
diameter One side of the neck is evagmated
to form a shallow reservoir In use the bulb
is compressed and the shield is placed against
the breast so os to enclose the nipple On
release of the bulb, milk u sucked out
through the nipple Rccompression of the
bulb allows the milk sacs to rchU so that the
procedure can be repeated until no further
flow of milk IS obtamed The milk may be
desired for a baby who cannot nurse, m
which ease the pump should first be sterilized
by immersion m boiling water for 10 mmutes
or should be otherwise suitably disinfected
Breast pumps may be used when a baby is
weaned temporarily because of illness of the
mother or because the baby is unable to
suckle sufficiently to dram the breasts of mdk
at each feedmg It is necessary to empty the
breasts completely, since failure to do so
regularly will result ui a drymg up of the
milk secretion Manual espfcssion of breast
milk by the mother is a less traumatic and,
therefore, a preferred procedure, a breast
pump should not be supplied without advice
from the physician la aitcodancc
The urethral syringes used currently arc
largely of the bulb type, the plunger type hav-
ing been superseded by this more easily
handled form The syrmge barrels arc gen-
erally of glass for ready sterilization The
Asepto* urethral synnge is available in sizes
ranging from Vi ounce to 1 ounce and with
blunt or tapered glass tips as well os soft
rubber tips The neck of the bulb fits msidc
a Oared end of the glass barrel (Fig 143)
and has thick walls the better to maintain
Its shape The capacities of the bulb and the
band ate adyusted so that one full com-
pression fills or empties the barrel without
drawmg Ouid mto the bulb Two small side
openmgs m the removable Bakelile plug in
the neck of the bulb allow movement of air
but hinder flow of fluid into the bulb Other
Asepto syrmges are available with capacities
up to 4 ounces, with special ups for attach-
ment to catheters or hypodermic needles, or
tor uTtgaUag the eye and other body caviucs,
so that they arc of general uuhty
The medicme dropper is a bulb synngc
which the pharmacist handies so frequently
that the usual forms require no dcscripuon
The oJIidoJ medicine dropper is defined by
the United States Pharmacopeia'^^ as havmg
a delivery end 3 mm in external diameter
and delivering 20 drops of water weighing
1 Gm at IS® C Droppers vary m size and
form of bulb and m length, curvature and
style of Up, those to be used for mstilling
drops into the nose or the eye have blunt,
flared or ball ups Droppers attached to
dropper bottles often arc not standard This
may give the pharmacist cause to wonder if
the amount of medication delivered in the
number of drops stated on the presenpuon
label IS actually that mtended by the pre-
senber One manufacturerf advertises that
hts bottles have polyethylene tubes designed
to deliver according to USJ* standards It
• BcctoD, DicLiiuoa and Company, Ruiherford
N J
t Armstrong Cork Company, Lancaster, Pa.
Rubber and Plastic Accessories
421
Fig. 144. {Left) Ure-
thral catheters. From
left to right: 30F Rob-
inson 2-eye hollow tip
x-ray opaque rubber
catheter (eye on oppo-
site side dotted in with
white paint); 30F 1-eye
solid tip rubber cath-
eter: 24F 1-eye coude
olive tip rub^r cath-
eter; 14F 1-eye Nylon
woven catheter with
male thread at tip; S-tip
Nylon woven filiform
with female thread to fit
tip on Nylon woven
catheter. {Right) In-
dwelling catheters. From
left to right: Foley cath-
eter, 18F, 5 cc. balloon
inflated; Foley catheter,
18F. 5 cc. biloon, not
inflated; Foley catheter,
30F, 30 cc. balloon in-
flated; Malecot tip cath-
eter, 30F; Mushroom
tip catheter, 30F.
should be noted that these polyethylene
droppers soften and collapse at autoclave
temperatures and, thus, are not suitable for
preparation of sterile ophlhalmics. An inter-
esting development is a flexible one-piece
vinyl chloride medicine dropper* developed
for one-time use in hospitals. These ate
actually reusable, since they are easily rinsed
and can be boiled for 5 minutes or auto-
claved for 10. The dropper meets VSJ*.
specifications for size and for delivery of
water.
Mandrel Goods
Items such as catheters, tubing, rubber
gloves and other rubber goods are often
made by applying thin coats of rubber to the
outside of forms (mandrels) immersed in
fluid dispersions of rubber. A mandrel may
be made of porcelain, glass, varnished wood
or metal. In one method, the mandrel is
dipped into a latex dispersion, then removed
to allow drying of a thin layer of rubber on
*TFL CUqIc Dropper, Thomas Fazio Labora-
tories, Auburadale 66, Mass.
its surface. Successive dippings by hand or
machine follow until the desired thickness is
built up. In the electro-deposition or anode
process, a metal mandrel is made a positively
charged anode so that it collects on itself a
coating of the electronegative rubber par-
ticles. Mandrel-made items are generally
vulcanized by heat while still on the mandrel.
Tubmg, High grade rubber tubing is made
from latex by the anode process. Much of
the tubing on the market is molded, often by
an extrusion process, from rubber of varying
quality and with formulations modified for
specific purposes. It is often colored and
may have exterior ribbing. That designated
as “floating stock” is the purest form in the
sense that it contains a low amount of sulfur
and mineral fillers. ^Vhilc internal diameters
of tubing usually range from 1/16 to inch
with wall thiclmcsses of 1/16 to Vi inch,
tubings with dimensions different from these
arc made for specialized uses. Tubing is
marketed in 2S-foot or 50-foot rolls, in boxes
or on reels. It is also available in shorter
lengths — as 5-foot replacement tubing for
422 Pretcription Accessories and Retaled Items
fountain s)nngcs, for example Tubing has
many uses, from general lalxiratory work, to
conducting intravenous solutions hfuch tub*
mg IS now made of plastics rather than
rubber
Urethra] catheters are tubes which arc m*
troduced into the urethra m order to dram
the bladder or to mjcct fluids into it They
arc made of wo\cn fabrics (silk, linen,
n)lon), metal, glass, s)’nthcuc rubbers (nco*
prcnc) and plastics (pol 3 cth)]cnc, vinyl) as
well as of hard or soft rubber In order to
provide cxlrctncly smooth inner and outer
surfaces, rubber catheters arc made by the
anode process or, m some eases, by molding
o\cr glass tubmg Catheter sizes are desig*
nated accordmg to scales named after the
country of origin (Table S8) On the French
scale — which is the one most commonly re-
ferred to— catheters run from 10 to 22 They
arc 10 to 12 mehes long and arc uniform m
caliber throughout their length except that
there may be a funnel-shaped openmg m
some styles The tip is variable, being round,
olive or conical (for example), and it may be
solid or hollow with one to several aper-
tures (eyes) (Rg 144)
Careful study of the manufacturer's cat-
alogs IS necessary to become familiar with
the many styles available A fairly stiff oon-
elastic catheter, sometimes especially curved,
IS often easier to insert into male patients
because of bends and stnclurcs m the rela-
tively long urethral passage Flexible cath-
eters of softer rubber arc used in females
where the shorter urethra causes fewer prob-
lems Sizes I8F and 20F arc normally used
for adults, lOF and I2F for children A wire
stylet (or mandrin) may be used to un-
part rigidity to a rubber catheter during in-
sertion It IS withdrawn after insertion, leav-
ing the catheter m place The flliform catheter
has a long flexible tip (Fig 144, left) which
males Its way past strictures and coils up in
the bladder while the mam part of the in-
strument follows Its lead X ray urethral
catheters ore impregnated with lead or bis-
muth salts so as to cast a shadow under the
X ray Some catheters have calibrations on
the outside, so that distance of insertion is
readily determined Double-channel instru-
ments have two lumens so as to permit in-
flow and outflow for irrigation purposes
Self retaining or indwelling catheters have
been designed to decrease need for recurrent
catheterization The Foley catheter (Fig 144,
nght) IS the most used In addition to the
main lumen, there is a smaller one which
connects to an inflatable rubber bag near the
catheter tip After insertion, air or water is
passed into the rubber bag making it loo
large to slip back through the vesicle openmg
The catheter will remain supported m place
until the bag is deflated to penmt removal
Either constant or mtcrmittent drainage can
be established Creevy** has selected five
catheter styles which he says arc satisfactory
to fulfill all the needs of on active urologic
practice and desenbes their use
Cathetcis must be stenle and aseptic
technics must be used dunng insertion Lu-
bneauon is always necessary, a sterile water-
soluble jelly* being preferred to petrolatum
or mineral oil for therapeutic reasons, as
well as for lessened damage to rubber cath-
eters A recent trend is the use of disposable
polyethylene and vinyl catheters These are
sealed into mdividual plastic envelopes and
then sterilized with ethylene oxide
While opinions on the danger of catheten-
zation vary greatly, the catheter has been
called the most common agent responsible for
resistant urinary mfcctions Insertion of a
urethral catheter is a procedure requiring
skill and cxpencncc beyond that of a lay
person, and must be done by the physician
or the nurse Because of the specialized
knowledge required for their use and also,
perhaps because of their misuse m attempted
self abortions, catheters arc classified as
legend "drugs," a prescription bemg required
for their dispensmg
Stomach tubes arc 60-tnch long, soft rub-
ber tubes intended for passage into the
stomach for purposes of removing its con
tents, for gastric lavage or for mlroducing
liquid food or medication These tubes have
one cy c near the open tip and a widely flared
funnel-opening at the other end There is a
depth mark 18 inches from the up In addi-
tion to this style, there is a design in which
the tube is cut into two approximately equal
lengths which arc then joined through a
* Lubsfox stenle surgical lubncant in a 2.7 Cm
•lagle use foil package u available from Durrougbs
Wellcome and Co Tuckahoe, N J
Rubber and Plastic Accessories 423
valved aspirator bulb Stomach tubes are
Sized accordmg to the French scale, the small
22F being used for children, while sizes 28F
to 32F are available for adult use Whfle m-
sertion of the stomach tube is usually reserved
for the physician, gastnc lavage is a term
familiar to phannacists as a part of the
emergency treatment of poisomngs The
stomach tube is first placed m ice, smce a
stiff, cold tube is passed more easily Some
recommend lubncatmg the tube with a vege-
table oil, though oils may mcrease the tend-
ency to nausea The tube is placed far back
m the mouth of the sitting or recumbent pa-
tient As he swallows, the tube is advanced
until the marker is reached, mdicating that
the end is m the stomach There is danger of
damagin g the larynx or perforatmg the esoph-
agus or the stomach If the patient is un-
cooperative, a smaller tube may be passed
through the nose Lowermg the funnel end
below the level of the tip will siphon out the
stomach contents The funnel is then held
upright and about 500 ml of irrigating fiuid
(water at 105^ F , usually) is added, kern-
mg the funnel full To siphon again, the
funnel is mverted and lowered while there is
still some fluid m it, smce this avoids the
mtroducuon of air which may cause disten-
tion and pauL This alternate dilution and
dramage is repeated until the wash fluid is
clear or until a prescnbed amount has been
given As much as 3 gallons may be used
Finally, the tube is pmched off at the pa-
ticnt's bps and quickly mtbdra»’a Alter
use, It IS cleaned and disinfected by usual
procedures satisfactory for rubber
Duodenal tubes are provided for insertion
by way of the nose, usually mto the upper
part of the small mtestine to sample its
contents or to remove gas and fluids m
the prevention or the treatment of disten-
tion following abdommal surgery Suction
by an aspirating device is used m this pro-
cedure The Levm tube is a flexible, soft-
walled, 4 foot tube, sizes 10 to 18F, with 4
side e)es near the tip and with concenliK
markmg rings usually 19, 23, 27 and 31
mches from the tip The Cantor tube is an
18F, 10 foot tube with a small mercury filled
bag at Its multiple-eyed tip The “mushy”
heavy balloon is mtended to stimulate open-
mg of the p)lonc val>c and to permit ad-
vanemg of the tube by gravity The aspirator
is started when the letter ‘ S” on the tube is
at the patient’s nose The MiUer-Abbott*^*
tube is a metal tipped, 16F, 10 foot, double-
lumen tube, one lumen openmg mto a small
balloon near the tip Markings on the tube
are to mdicate the distance it has been passed.
An eye at stomach level, as well as one at
duodenal level allows dramage of both The
tube IS passed through the pylonc valve with
the balloon deflated, then peristaltic action
carries the inflated balloon and the tube along
the mtestme Dam rubber reservoirs to ac-
cept aspirated flmds are at the upper end
Many modifications of these basic designs,
including some with magnet tips, are avail-
able
Rectal tubes superficially appear to be
large urethral catheters They are made of
flexible rubber and always have an openmg
on the tip as well as one eye near the Up
and a funnel-opening on the other end. They
are 20 mches long and are available m sizes
16F to 32F, with 22F and 24F most often
used for adults The rectal tube is attached
through supplemental tubmg to an imgatmg
can or to a fountam synnge for givmg an
enema. The up end is lubneated and mserted
mto the rectum for a distance of about 4
mches Higher inseruon serves no purpose
and may be dangerous The relaUvely long
leng^ of the rectal tube is to provide flexi-
bility and some degree of control rate of
fluid flow by finger pressure Rectal tubes
are less likely to cause injury to the rectum
than are the hard inflexible tips usually sup-
plied with fountam synnges, therefore, the
pbannacist can do his patron a service by
tellmg him about them
Colon tubes are larger and heavier-walled
rectal tubes They are 30 inches long and
range m size from 22F to 32F These tubes
are used to remove feces &om the lower
colon by imgauon m much the same maimer
as are rectal tubes They are also used to
mtroduce fluid food mto the lower bowel
Rubber Globes. Stenle rubber gloves are
used by physicians and nurses to guard
against contammation of wounds and to pro-
tect their hands from pathogens or unpleasant
discharges while exammmg body areas Sur-
gical gloves are made from natural latex by
&e anode process to secure the thm walls
42-4
Prescription Accessories and Related Items
Fio 145 {Leji) Nipple shield (.Right)
Dreast shield
necessary for freedom of motion and sensi-
tivity of touch Sizes from 6V6 to 10 allow
for the desirable snug fit. The gloves may be
sterilized by autoclaving for 15 minutes at
250° F Procedures for obtaining maximum
glove life have been worked out Washmg
with mJd soap or detergent and nnsing arc
followed by drying mside and out Holes arc
detected by visual inspection, air testing or
electrical methods Prior to autoclaving,
the gloves arc powdered inside and out to
prevent sucking on exposure to steam
Talcum or an absorbable powder prepared
by processing cornstarch* are often used
gloves arc wrapped as individual pairs
m muslin or m autoclave paper along with
a packet of glove powder which will used
when the gloves arc donned All air should
be exhausted from the autoclave durmg
sterilization As little as 0 I per cent of air
remaining m the steam chamber will double
the rate of deterioration of the gloves Smcc
the glove rubber temporarily loses its strength
because of being heated, gloves should not
be used for 24 to 4S hours after autodavmg
Eth)lcnc oxide stcnlizaUon at 130® for 4
hours*^ followed by a post stcrilizauon rest
period of 8 to 16 hours is also used Gloves
should be stored m a cool, dark place Care
must be taken to avoid puncturing gloves
with the fingernails v hilc handling Surgical
gloves arc removed fi ini the hands by rolling
them inside out, rather than by pulling them
off Disposable pol}cth)lcnc and polyvinyl
gloves m prcstcnlizcd unit packages arc now
rclauvciy inexpensive and ore becoming more
widely used, especially as examining gloves
Rubber gloves for household, garden or
work use are also manC.'cl made, but usually
by dippmg proccdutes Walls arc thicker tlion
* Dioiotb. Eihicoo, Inc , Somen-j N 1
for surgical gloves, fingers may be reinforced
and roughened on the outside, and the mside
may have a special lining for ease of don-
ning Small, medium, large and extra large
sizes are marketed Synthetic rubbers such
as neoprene, which resists oils and greases,
as well as various plastics arc widely used
Such gloves arc appropriately stocked in a
pharmacy, since they are used to protect
hands against detergents and common irri-
tants
Finger cots arc rubber finger-shaped
shields wihich are used m Ueu of gloves to
protect fingers against corrosives or to pro-
vide a nonslip grip for work such as sorting
or filing Thin walled cots are made from
natural latex rubber by a mandrel process,
while thicker ones for heavy work arc made
from other rubber formulations or from
neoprene Usual sizes are small, medium,
large and thumb A cot which is too small
can seriously interfere with blood circulation
Tlic pharmacist should discourage the use of
finger cots as a wateiproof covering over
bandages, since they prevent ventilation
Nipple Shields. A nipple shield (Fig 145)
IS a round, slightly convex glass or plastic
plate with a short central upwardly project-
ing tube to which a rubber nipple is securely
attached The nipple is mandrel made The
shield is intended to be placed over sore
nipples so that the pressure of the nursmg
baby’s mouth wdl be attenuated by the re-
sistance of the rubber nipple This device is
not very satisfactory for either the mother
or the baby, so it is used only when gross
imtation or fissures arc present The breast
shield (Fig 145), made entuely of rubber
and shaped much like the nipple shield, docs
not provide for nursmg It is worn to protect
inflamed or imtatcd nipples from contact
wiihclothing
Condoms. The condom or prophylactic
IS a thin, nonporous sheath which is worn
over the ptnis during coitus A legal defini-
tion of the term prophylactic includes “any
dcviw, appliance or medicinal agent used in
the prevention of venereal disease"*^® Be-
cause of the public health aspects inherent m
the use of condoms, many states in this
country have established standards of
quidity for these articles and test them regu-
larly. About 16 states restrict their distnbu-
tioa to regular drug channels Since condoms
Rubber and Plastic Accessories 425
prevent the deposition of semen mto the
vagmal canal, physicians may prescnbe their
use when voluntary control of conception is
necessary for obstetnc or gynecologic rea-
sons
Sheaths made of rubber and of animal
membranes are most widely available m this
country A film*®’^ depicting the production
of rubber prophylactics by a latex process is
distnbuted without charge for showmg to
select groups Glass mandrels are dipped
mto a dispersion of latex, heat-dned and re-
dipped to make a sheath with a diameter
rangmg from 1 Vi to 2 inches and with a wall
thickness of about 0 002 mches A narrow
bead is formed by rolling the open end on
Itself, leaving the tube slightly more than 7
mches long Sheaths are heat-cured while on
the mandrel DusUng with talcum powder
prevents sticking together of rubber surfaces
The sheaths are placed on metal mandrels
and passed through an electrified bath to de-
tect and eliminate those with holes Ihe m-
dividual condom is rolled mto a flat nog
which may then be sealed m aluminum fed
or otherwise encased Usual packages are
paper envelopes, cardboard boxes or metal
contamers with 3, 12 or 36 condoms In a
cement process which is used by one com-
pany m this country, glass mandrels are
dipped mto a solution of crepe rubber m
benzol or gasolme,^"* then the rubber is
vulcanized at high temperatures There is
controversy as to the relative ments of the
two processes A special shape of prophy-
lactic, the receptacle end condom, termmates
m a short narrow pouch — about 1 x %
mches — which, m use, extends beyond the
tip of the perns This is claimed to reduce the
possibihty of breakmg the sheath, smee the
semen is ejaculated mto the open chamber
rather than against an end which may
be stretched tautly if the user of the regular
condom does not allow a temunal margm
Receptable end condoms may be dry or may
be lubricated before packagmg The exact
composition of the lubncant is a manufactur-
mg secret, but the fluid is aqueous and gen-
ei^y contams gljccnn and a preservative
Lubneauon is mtended to compensate for a
possible dryness of the vagmal canal and is
therefore stated to mcrease sensitivity
Condoms made of animal membranes are
about the same m general dimensions as
those of rubber except that they may be
slightly thinner walled Details of manu-
facture are not available These * skms” are
made from a natural pouch, the “cul” or
cecum of the lamb The pouches must be
cleaned and defatted to prevent deterioration
and the development of noxious odors Smee
they are not elastic, rubberized thread is sewn
along the nm of the open end Skms are
generally lubricated and rolled before pacL-
agmg Animal membranes are claimed to
conduct heat better than rubber and, there-
fore, to mterfere less with normal responses
They are more costly than those made from
rubber
Misbranding and adulteration provisions
of the Federal Food Drug and Cosmetic Act
apply to condoms which pass m mterstate
commerce State regulations, where they
exist, are often more specific In California,
for example, minimum dimensions of sheaths
are specified and sample prophylactics must
pass a water lest’*'’ Prophylactics are re-
quired to be labeled with the name and the
address of the manufacturer and also with the
date of manufacture No prophylactic may
be oflered for sale when the dating mdicates
It was manufactured more than three years
pnor Storage of prophylactics should be m a
cool place removed from sources of heat or
ozone Contact with petroleum jelly or
oils can be expected to brmg about detenora-
tion of rubber prophylactics
Diaphragms. The vagmal diaphragm is an
oedusive device which the woman apphes
over the cervical openmg pnor to coitus It
IS used only for contraceptive purposes
Diaphragms are generally made of ihin latex
rubber molded mto a domed circular shape
and rimmed with a steel spnng enclosed m
heavier rubber Available models differ m
shape, depth, kmd of rubber and m type,
thickness and tension of spnng When prop-
eriy positioned, the lower part of the dia-
phragm nm rests m the postenor fonux and
the upper part lodges behmd the symphysis
pubis so as to hold the diaphragm securely
in place The diaphragm does not allow
sperm to be deposited directly at the cervical
openmg but it cannot be expected to prevent
them from passing around its run A contra-
cepti'ie jelly or cream must always be applied
to Its surfaces and run so that sperm must
travel m the spermicidal preparation for at
426 Prescription Accessories ond Reloted Items
least the diameter of the diaphragm before
reaching the os It ts the increased duration
of exposure to the spermicide >\hich con>
tnbutes to the ciTectivcocss of this method
To afford adequate protection the size and
the 1)^0 of diaphragm must be selected for
the patient by the physician after a gyne-
cologic examination to determine the depth
of the sagina, the lone of the perineum and
the condition of the pelvic organs The dia-
phragm N^hich IS either too small or too large
IS not properly supported and the penis may
pass betivccn it and the symphysis to release
sperm at the cervical os Because of the
need for individual fitting and for instmc-
lion m proper insertion, Federal law stipu-
lates that these devices may be dispensed
only on prescription Diaphragm sizes,
designated m terms of the diameter in milli-
meters, range from 50 to 105 m merements
of 5 Sizes 70 to 90 ore those most commonly
prescribed, with 75 the size most frequently
called for
The wearer is taught to mtroduce the dia-
phragm wuh her fiagcis, or she may prefer to
use an mserter specially designed for this
purpose** Most diaphragms may be used
cither dome up or dome down Before in-
sertion, about a tcospoonful of spermicidal
jelly or cream is spread on the rim and over
the side of the diaphragm which will contact
(he cervix or over both sides The diaphragm
may be inserted several hours pnor to coitus
and should be left in place for 6 to 8 hours
after It should be removed not longer than
24 hours oficr mscrtion Removal is suoply
accomplished by hooking the tip of the index
fmger over (he ontenor nm of the dia-
phragm and pulling down and ouL A cleans-
ing douche may ^ taken at this time, al-
though It is not necessary and, perhaps,
undesirable The diaphragm should be
washed with mild soap and water, nosed,
dned thoroughly, dusted with talcum powder
and stored in its contamcr It should be cx-
ammed for holes or tears before use Bod-
ing the diaphragm or cleansing with antiseptic
solutions IS neither necessary nor recom-
mended ••
Before dispensing a diaphragm the phar-
macist should alw'ays examine it carauUy
for defects or detenoratioo. If the presenp-
tion docs not cany complete mformatioo.
be should ascertam if the patient desires an
introducer and a vaginal cream or jelly Kits
contammg these along with the diaphragm
are avaJable A supply of talcum powd^cr
may be suggested as an adjunct to proper
care of the diaphragm Since a diaphragm
may last about 2 years, the pharmacist may
be well advised at the time of the ongmal
dispcnsmg to tell the patient that permission
of ^c presenber will be needed when replace-
ment IS necessary
Cervical caps arc soft rubber, plastic or
metal cups made to fit over the cervical open-
ing Suction may play a part m holding cer-
tain types in position They arc frequently
left in place for days or even longer without
mjury^® Cervical caps may be used m
some eases where anatomic abnormalities
prevent the use of a diaphragm Although
they arc in common use m Great Britain and
Central Europe, they do not appear to be
well known to die lay public m the United
States They may be dispensed only on
prcscnption
Conlraccpbve Agents. Compositions and
uses of contraceptive jellies, creams and sup-
posiloncs have been reviewed annually
Some products arc designed to be used as the
sole contraceptive agent, while others must be
applied to a diaphragm or placed inside a
condom. A translucent syringe applicator
may be supplied to facilitate deposition of the
jelly or the cream (about 5 cc.) m the
vagina. Commercially available formulations
have been reported and tested by m vitro
methods ** ** Vanabics inherent m actual
use situations do not appear to be amenable
to the rigorous control necessary for chmeal
studies capable of unequivocal determination
of either the absolute or the relative efficacy
of the several chemical and mechanical con-
traceptive methods which have been de-
vised” Phjsicians seem to make a
choice based on a sort of clinical ‘sixth-
sense ” No pharmacist should recommend a
contraceptive product or method
ELASTIC SUPPORT ITEMS
Orthopedic supports require detailed ex-
position and demonstration for adequate ex-
planation of uses and fitting for specific
individual conditions Nooethclcss, there are
Elastic Support Items 427
certain elastic support items which are
stocked by pharmacies because they are used
without medical advice Elastic hosiery,
anklets, knee caps, wnst and elbow supports,
athletic supporters and suspensories faU mto
this category Elastic bandages will also be
discussed at this pomt because of similanties
m construction and use
Elastic bandages* may be made with rub-
ber threads woven mto the fabric, or, altema-
Uvely, the elasticity may be due to a special
kmt of cotton fibers These bandages are
used chiefly to apply compression to sprains,
vancose veins, bums or wounds and nb
fractures The elasticity allows the bandage
to “give” if swelling occurs under it, so that
mterference with circulation is minimized
Greater pressure may be applied with the
rubber-contauung bandages, but they are less
porous and, therefore, make the covered area
warmer All-cotton bandages are less sub-
ject to deterioration from heat and light, and
washing restores the elasticity Both types are
available m widths of 2 to 6 inches or more
The usual length is 5 Vi yards, stretched
Ends are fastened m place by flat, pronged
metal clips which are furnished with each roU
of bandage Replacement, clips should be
stocked, smce clips are easily lost or broken
At least one brandf now is marketed with
a clip permanently attached to one end.
Adhesive elastic bandagest are adhesive-
coated cotton bandages with somewhat the
same uses as those delmeated above, as well
as those usually thou^t of for adhesive tape
Widths vary ^m 1 inch to 4 mcbes and
lengths are up to 5 yards stretched.
Elastic Hose. Elastic hosiery is worn to
prevent or alleviate vancose veins These
develop usually m mdividuals such as den-
tists or pharmacists who may be required to
stand m one place for long penods of time
Alternate contraction and relaxation of leg
muscles during walkmg help the return flow
of blood to the heart against the force of
*Ace Elastic Bandages, B D Cotton Elastic
Bandage, Bccton, Dickin^n and Co Rutherford,
N J , Adaptic and Comprol Elasuc Bandages
Johnson and Johnson, New Brunswick, N J
t Tensor Elastic Bandage, Bauer and Black,
Chicago lU.
tAce-bcsi>e, Bectoo, Dickinson and Co,
Elastikon, Johnson and Johnson.
gravity by massaging vein walls so as to
sqiKeze the blood along through a senes of
v^ves which tend to direct it upward only
With contmued standmg, blood accumulates
m the leg, venous pressure mcreases, the
valv^ fail, the walls of the effected veins
bulge and knot as they become distended by
the blood and severe pam is felt. The com-
pression and the massaging action of elastic
bandages or hosiery are used to help the
leg muscles m retummg blood to the heart
and thus give symptomatic relief and prevent
further unsightly venous distention
ElasUc hosiery is kmt from latex rubber
thread covered with nylon, rayon or cotton
Brands and styles differ in details of design,
m gauge of rubber thread used and m weight
and type of kmttmg yam An elastic stocl^g
may have either two-way or one way stretch,
the latter lackmg lengthwise stretch One-
way stretch stockings are generally of heavier
weight and dehver maximum circular com-
pression which makes them better suited to
treat severe or difficult cases Men do not
object to tbeir bulkiness, but women find
them unattractive and often refuse to wear
them m public Smce there is no vertical give,
the one-way stretch stocking must be fitted
very carefully so as to provide uniform pres-
sure Failure to do so may cause edema or
other compbcations m spots where too httle
pressure is being applied Individual manu-
facturers supply diagrams to show the key
parts of the leg to measure and correspond-
ing tables to enable choice of the correct
stock size Snug measurements accurate to
H inch should be taken without compressing
the leg If swellmg occurs during the day,
circumference measurements should be taken
by the patient in the morning before arising
Two way stretch stockings are available
m surgical (heavy) weight, service weight
and m sheer light-weight styles Fitting to Uie
leg IS easier, smce the more the hose is
stretched lengthwise the smaller its circum-
ference becomes A few measurements are
taken to choose from among the 4 or 5
available sizes rangmg from small to extra-
large As the thickness of the cloth decreases,
therapeuUc support docs likewise It is doubt-
fiil that the ultra-sheer style which vanity
persuades women to choose actually provides
adequate compression. They should be en-
428
Prescription Accessories ond ReJoled Items
Fio 146 (Top) Elastic hose Left lo
right, overknee, lighlss eight, two-way
stretch, tiiU (oot reandcss ayloo clasuc
hose, similar with partial foot only, simi-
lar underknee (garter) length, surgical
weight one-way stretch, garter length,
rayon and cotton hose (Bottom) Ex-
tremity supports Left to nghi, knee sup-
port, ankle support and wrist support
counged at least to wear a heavier stocking
while at home.
Both forms of stoebng arc available in
lengths langtng from bclow-kncc of garter
styles to thigh hose, and considcratioo must
be given as to where the support is needed
(Fig 146, wp) Some have a full foot, but,
more often, the toe and, sometimes, the heel
arc cut out so that a pair of dress hose may be
worn over them Seamless hose is popular
because it is more easily covered
Elastic hose is put on by rolling or folding
it down until the foot may be inserted easily
into the toe end and then rolling it back up
the leg with a minimum of tugging and pull-
ing &mc wearers, m order to prevent swell-
ing, need to put on the hose before arising
Proper care of the elastic stocking is im-
portant, smee the rubber m it is subject to
deterioration from oils, heat and other envi-
ronmental factors mentioned previously
Daily washing with soap and water, adequate
rinsmg and drying and a resting penod be-
tween weanngs arc desirable for maximum
life (ibnscqucntly, the user should have at
least two stockings for each affected leg
Extremity Supports. Anklets, knee caps
and elbow braces arc made of rubber thread
covered with cotton and woven mto seamless
surgical-ncight tubes shaped appropnately to
6t areas which each is intended to sup-
port (Fig 146, bottom) They are used most
often to compress, support and immobilize
sprains or wrenched joints Sizes run from
small to extra-large, with fittmg done by
having the client try on the support. Hinged
knee caps with jointed steel side-bars are
available to supply lateral support when
needed for severe sprains Wristlets (Fig
146, bottom) also arc used lo support a weak
wnsl and are available m leather as well as
in clastic cloth Leather wnstbands have one
to three straps, depending on their width, and
may be lined or unlmcd Elastic and leather
wnsUcts often arc made m a single size which
IS adjusted to fit the wnst. through snap
buttons or buckles
Suspcnsoncs are used for a wide vancty
of condiuons involving the scrotum and its
contents Conservative treatment of vanco-
cclc, epididymitis and orchitis calls for wear-
ing a suspensory They are also used to
support the scrotum after treatment of hydro-
cele and after hernia repair, prostatectomy
and scrotal surgery In each instance, the
function of the suspensory is to hold up or
to support the scrotum so os to relieve the
pam and discomfort attendant on the afUiC-
tions listed above
Suspcnsoncs consist of a pouch attached
to a body belt (Fig 147, left). Some also
Sickroom Utensils 429
Fig 147 {Left) Suspensory This style with leg straps is especially suited for active or
heavy set men {Right) Athletic supporter
have leg straps which provide additional sup-
port though they may cause some discomfort
to the wearer Pouches are made of soft
cotton knitted mto a porous mesh to permit
ventilation The pouch should be the conect
size to contain ^e entire scrotum comfort-
ably A pouch that is too small tends to bmd
and cut at the edges and to compress rather
than to support A pouch that is too large
cuts mto tissues around the scrotum and does
not give good support Since correct fit is
determmed only by observation from both
front and side with the patient m a stand
mg position, the original designation of size
may be made by the attending physician
Pouch sizes range from small to extra large
Some styles have drawstnngs which allow for
nunor adjustments Belts may or may not
be elastic but are always adaptable to a wide
range of waist dimensions Size designations
do not refer to belt length but only to pouch
capacity Vanations b^ctween suspensories
are found m weight of pouches, form of body
belt and presence or absence of leg straps
Catalogs suggest that some styles are better
for stout men and others are better for
slender men
Athletic supporters are worn usually os
scrotal supports to combat fatigue and strain
durmg sports or other tinng physical activ-
ities They differ from suspensories m being
made of clastic cloth (cotton or nylon) and
m bemg designed to enclose all the gcmtal
organs wiihm the pouch rather than only the
scrotum (Fig 147, right) Some arc made
with a nonelasuc butted mesh pouch Both
pouches and leg straps are generally an m-
tegral part of the appliance, but they are
detachable m some styles Belt widths vary
from 1 mch up to 10 mebes with the wider
belts bemg used as abdominal supports,
sometimes for a “s limmin g** effect Sizes are
m terms of waist measure, not pouch size,
and run from small to extra large Supporters
are easily fitted, smee the elasticity of the
waistband allows for a range of 2 to 3 mebes
witbm each size As with ^ apphances con-
tauimg rubber, proper care to avoid contact
with detenoratmg agents will extend the
penod of useful service
SICKROOM UTENSILS
Proper care of a person confined to bed
may require the use of several forms of pans
or basms for collecting body excretions and
discharges This ware is made commonly of
stainless steel or porcclam enamel and, some-
times, of gloss, rubber or plastics
Bedpans (Fig 148, top) are fanly shallow
pans which are slipped under the hips of a
person lymg m bed so as to collect his feces
and urmc They are generally oval m shape
and have a wide ffat nm for supportmg the
weight of the mdividual Both adult size and
duld size pans are made. A specially angled
430 Prescription Accettones ond Reloied Items
rto 14S (Top) Dcdpjfl (Je/l) and
fracture pan These ore sUonlcss stcc!
{Douom) Male (left) and fcrtulc caaincl
urinals
st)lc* said (o be less uncomfortable is avail*
able The fracture bedpan (Fig 148, top) is
smaller, flatter and easier to use with tm-
mobilizcd or oserwcight patients or children
Those of stainless steel arc most suited to
continued and rough usage as m hospitals
Enamclware is acceptable for home use,
though heavy, cold and easily chipped, it is
cosy to clean Rubber inflated bedpans arc
sv ann and comfortable, but are expensive and
difficult to clean Plastic bedpans arc light,
warm, sturdy and easily cleaned, so these
newly available forms seem ideal for home
use Autoclavablc pans are molded from poly*
propylene nonautoclavabic from polystyrene
The purchaser may need instmctioo m the
use and the care of a bedpan Steel or coomcl-
warc should be warmed before use by wash-
ing with warm water and then drying It is
advisable to spread several layers of news*
paper under the patients hips as a precau-
tion against acadcntal spillage Immediately
after use, the pan should be cleaned, dried
and made ready for reuse
Douche pans have the general appearance
* Relax Bedpan The Jones Meul Product* Com
pony WcsxLjrjyctte, Ohio.
of fracture pans, but arc flatter, shallower
and more oblong They arc used to collect
medicated solutions or washes following
irngations of body cavities
Unnols arc employed to collect urme The
two types, the male and the female, differ
in shape as shown (Fig. 148, bottom).
They are made from stainless steel, porce-
lain enamel, glass or plastic Some arc cali-
brated to /acdiCatc mcasunng (he volume of
unne output when requested by the physi-
cian They hold about 1,000 ml m the
honiontal position Unnals should be
warmed before use m the same manner as
bedpans and similarly cleaned after use
Autoclavablc plastic urinalsf arc now avail-
able
Kidney basins arc so named because of
their shape They arc also called emesis, pus
and sputum basins after the fluids commonly
collected in them The usual capacity is 500
(o 1,000 ml Inexpensive kidney basins of
plasuc or treated paper are available, these
arc disposed of after each use
Other utensils and equipment which phar-
macists should supply— since they are needed
for taking care of bedridden patients — in-
clude wash basins, foot tubs, serving trays,
feeding cups, water pitchers, drinking tu^s
or flexible straws and graduated measures
ELECTRIC HEATING PADS
For reasons of convenience and easy ad-
yustment of temperature, electric healing
pads arc now popular for home use Signifi-
cant diflcrcDCcs m design exist among the
av-adablc models withm any one brand of
beating pad. For example, a pad may be con-
structed to be either moisture resistant or w ci-
piDof, U may be a three-speed, a three posi-
tive heat or a variable heat pad These terms
are clarified in the descriptions which follow
The pad usually consists of a heatmg clc-
inem, at least two thermostats, a switch, a
cord^t, a plastic or rubberized cover and a
cloth cover The heating element is a re-
sistance wire which is wound over on insulat-
ing core and then covered with an insulating
bycr of matcnal to make a strand about three
t PluU cnctlic Manufacturing In« PasoJen*
Catifonua The Jones Metal ProJucu Compaa/
West iM*)CUe, Ohio
Electric Heating Pads 431
millmieters m dumeter This is sewn to a
flat piece of matenal, usually burlap A spiral
rectangular or, alternatively, a back and forth
pattern is followed to ensure even distnbu-
tion of heat over the whole pad The thermo-
static controls and the cornet are attached,
then the unit is covered on both sides with a
layer of soft cotton wadding backed with an
open-mesh gauze layer and the whole umt
is sewn togeUier along the edges The flat pad
IS enveloped m a totally enclosed cover
(usually a rubberized fabric or, sometimes,
vmyl) and sealed m a vulcanizing press or
a bi^ frequency sealmg machine to make it
wetproof These pads are immersed m water
to meet quahty-control standards for mois
ture leakage • It has been claimed that 22 of
42 models selected for test were not fully
sealed against moisture, the fault usually
bemg at die power-cord entrance Moisture-
resistant pa^ are built m the same manner
except that the cover is not completely
sealed and they are not given an immersion
test One or two cloth covers are placed m
the box along with the pad.
The switch selector on the 3-speed pad
may be marked low, medium and high, but
these refer not to the flnal temperature of
the pad but, rather, to rate of temperature
nse No matter which setting is used, the pad
will eventually attam the same temperature
(approximately 165 to 180° F) Only the
speed at which the pad heats up is con-
trolled The pad has tv^o heater circuits which
differ m resistance and by switchmg from one
to another or by switchmg both circuits m
parallel, the time required to obtain the de-
sired temperature is varied (Fig 149, top)
One of the two thermostats functions to
operate the pad at the desired temperature
and the second one is m the circuit as a
safety backup m case the operating thermo-
stat becomes defective and fails to open the
circuit On the other hand, through different
circuitry,*®* the ihrec-positive (or fixed) heat
pad does attain a separate and distmct sur-
face temperature for each different switch
selector position (Fig 149, bottom) Tem-
peratures are reached m 15 to 20 minutes
Pads differ m design of control switch,
* Standard for Electrically Heated Pads and
Bedding. UL 130, Dec. 1954, Underwnters Labo-
ratones Inc . Chicago, IlUnois
Fio 149 (Top) Typical temperature
time cbaractensUcs of a three speed elec
tnc beatiog pad (From Little L. D , and
Wise, R A , General Electric Co , Ashe
boro, N Carolina) (Bottom) Typical
temperature time characteristics of a
three positive heat electric beating pad
there bemg pushbutton, slide, contmuous
rotary and click-stop rotaiy types Switches
may have a glow light or raised ‘ braille”
markmgs to help m heat selection m the dark.
Covers may be made of cotton, acetate,
acrylic or nylon, they are generally washable
and are often beautifully patterned While
12 X 15 inches appears to be the standard
size, both larger and smaller pads are avail-
able Guarantees against defecuve workman-
ship and material range from 1 to 5 years
These are factors which, along with differ-
ences m basic construction features, are
measures of quahty or affect pnee The
waterproof pad is preferable because there is
less d^ger of shock to the user who perspires
heavily Furthermore, the waterproof pad
may be placed over a wet compress to supply
ste^y warmth and moist heat which may be
therapeutically desirable for inflamed areas
of the skm, for example A moist beat kit
consuting of a cellulose sponge and a double-
pocket cover IS available t On the other
t Mout Heat Kit Casco Products Corp Bridge
port, Cona
432 Prescription Accessories ond Reictcd Items
hand, the moisturc-rcsistani pad must be
kept dry, it must not be used Vitth VrCt dress*
mgs The three posiUsc heat pad is also pref-
erable over the three speed pad, smcc the
sclectability of the correct heat is desirable
for use over an extended length of tune
The pharmacist should be sure that his
client is warned about possible misuse of the
clcctnc hcaimg pad Precautionary state-
ments arc usually pnntcd on the box, these
should be emphasized at the time the pad is
dispensed Use of pins or other metallic
means of fastenmg the pad in place is very
dangerous because of the possibility of ex-
posure to clcctnc shock. For sunilar reasons
the pad should not be crushed or folded
while operaung nor should it be used if the
vm)l cover shows signs of blistering, crack-
ing or other damage It is important to warn
the user to examine frequently the area being
heated for unusual redness or signs of burn-
ing Cautions against going to sleep while
usuig the pad should be voiced, since serious
bums con result from this error
VAPORIZER HUMIDIFIERS
Vaponzcr-humidilicrs arc devices used to
produce steam and high humidity in the sick
room Both the moist heat and the increased
relative humidity*" arc considered bcnchcial
Inhalation of moist warm air is said to allevi-
ate inflammation of the mucous membranes
in acute colds and in sinusitis, to liquefy thick,
tenacious mucous and to relieve coughing**
The use of steam to relieve croup symptoms
IS standard •* Pediatricians not infre-
quently order vaporizers to be operated con-
tinuously hour after hour in the bedroom of
a ‘croupy’ child. Prolonged exposure to the
low relative humidity of artificially heated
rooms adversely affects the protccUvc mecha-
nisms of the mucous membranes of the re-
spiratory tract and contributes to the increased
incidence of upper respiratory infection dur-
ing cold weailicr** Simple humidification
may give relief to certain individuals with
acute or chronic respuatory disease ** Vapor-
izers often arc designed with a medicament
cup placed so that escaping steam passes
directly over it When aromatic matures such
os Compound Benzoin Tincture are placed
therein, the volatile mgrcdicots arc vaporized
by the heat and arc earned along to be m-
h^ed with the water vapor Good evidence
that these substances add to the therapeutic
action is lacking, and some practitioners be-
heve them to be unduly imtant to the respira-
tory tract.
Tlie basic components of a vaponzer-
humidilici are a jar to hold the water, an
clccincal unit to convert the water to vapor,
a lid with on escape hole for the steam and
a service cord to connect the clcctncal unit
to regular house current Jars are glass or
heat resistant plastic such as polypropylene
Luis are hard plastic usually The medica-
ment cup generally is hollowed out of the
portion of the lid immediately beneath the
steam escape hole A separate nozzle or
steam spout IS sometimes provided with the
vaporizer
For optimum performance a vaponzer-
humidilicr should begin to produce steam
within 2 or 3 minutes after being connected
to the source of clcctncity, it should reach
a steady rate of stcammg m 30 minutes or
less, It should vaporize about 10 to 16
ounces of water per hour, it should produce
steam for a relatively long time — ^perhaps 8
to 12 hours. It should shut off automatically
before the water level becomes too low, and
It should be safe to use, i c , wiUiout danger
of causing electric shock or bums Some
models meet these qualifications, others do
not ** The specifications for steaming rate
and durauon require a jar capacity of 1 gallon
or more A squat design with a broad base is
less likely to Up over accidentally
The iJircc types which are commcrciaUy
available differ in the way m which the water
vapor is formed In the electrolytic type (Fig
ISO, top), two electrodes arc immersed in
water which Uicn is heated as clcctnc cur-
rent IS caused to flow between the electrodes
In the butler type, an msulatcd heating ele-
ment is immersed in the water to heat it to
the boiling point The third type (Fig 150,
bottom ) docs not heat the water, but depends
on mechanical forces to break water particles
into fine vapor, thus producing a so-called
cold steam
Most electrolytic models have an elec-
trode assembly composed of the lid and of
the two electrodes suspended in a cylindncol
plastic chamber When this is inserted into
Vi\ 1 . ■
-’-j !
I'l-V 'yi yEr' /U?'
m
Fio. 150. (Top) Electrolytic vaporizer. The cap and the electrode assembly (lower
center) have been removed from the chamber (le/i). Note that the chamber is shorter
than the plastic jar with which it is used. Part of the cylinder of an adjustable-rate electro-
lytic model (lower rigltt) was removed to show the electrodes. At the low setting the
insulating plate is between the two electrodes. A, medicament cup; B, stationary electrode;
C, insulating plate; D, movable electrode. (Bottom) Cold steam vaporizer-humidifier.
( library
434
Pretcnplion Accettones and Related Items
ihe mam jar, %\ater flows into the plastic
chamber through a small hole in the chamber
bottom Only the rclau\cly small amount of
water m the chamber must be heated to boil*
mg m order to produce steam. This mokes
for quicker starting and also greatly reduces
the risk of bums or scalds, since the rest of
the water m the jar docs not get boding hoL
As the steam is generated it nscs through a
senes of holes at the top of the plastic
chamber and escapes ihrou^ the single targe
hole m the lid For safety, automatic shut-ofl
of the heating is assured by making the
chamber too ^ort to reach the bottom of
the jar; when the chamber is empty, cuncor
flow between the electrodes is not possible
even tiiough there is still water m the jar
Smcc the water is electrically live as long as
the electrodes arc m contact with it, the user
must be cautioned always to disconnect the
unit before lifting off the cover Some models
are designed to break the circuit automati-
cally when the cover is raised
The rale of steam producuon is propor-
tional to the rate of current flow between the
electrodes in the electrolytic models This, m
turn, depends on the quantity (and con-
ductance) of the ions in the water Failure
to understand this relationship u frequently
responsible for Jissatisfaciion on the part of
the user Tap water is rarely suitable The
high mineral content of hard water causes
frothing spdling over and a shortened dura-
tion of steaming, on the oUicr hand, soft (or
distilled) water conducts too poorly to pro-
duce enough steam The preferred procedure
IS to use distilled water (or soft tap water)
to which is added an amount of s^t. borax
or sodium bicarbonate adequate to impart
the correct conductivity Some companies
provide small salt tablets with the vaponzer
It IS usually necessary to start out with a
very small amount of clcctro])te and increase
It with successive uses until the performance
IS satisfactory A more selective control of
rate of steaming is alTordcd by those models
in which the space separating the two elec-
trodes can be widened or narrowed within
set limits by turning a dial on the hd (Fig
ISO, top) Increasing Uic distance between
electrodes (turning dial toward ‘low”) re-
sults m a slower rate of steam production,
smcc current flow is decreased. In clectcolytsc
models it is unportant to rinse the jar and
the electrode chamber with tap water after
each use so as to keep deposition of minerals
to a miDunum Even if this is done, it is
Usually nccessaiy after some SO hours of
operation to disassemble the electrode cham-
ber in order to scrape accumulated mineral
deposits from the electrodes
Boilcr-tjpc vaponzer huimdificrs also may
have the beating element incorporated wath
the lid Since, generally, all the water m the
jar IS heated, steaming may not start until
10 or more mmutes after plugging in the ele-
ment Also, the possibihty of being burned
increases when all the w'aier is heated to
boilmg Advantages of the boiler include
heating action mdependent of mineral con-
tent of water, water not electrically live, posi-
tive automatic shut'OlT by thermostatic con-
trol when the water level ^ops
In the cool vapor machme, an clectnc
pump sucks water from the reservoir tank, up
into a smaller chamber where rapidly rotating
metal vanes dash tlic water particles fores-
aw/ against a fine screen The vapor thus
formed nscs from adjustable cod or top vents
at a rate of 10 to 20 ounces per hour This
newer tjpc can use ordinary tap water and,
perhaps, has other advantages in design
which may encourage its being used despite
Its higher cost.
ATOMIZERS, NEBULIZERS,
INSUFFLATORS
Atomizers and nebulizers arc mslnimenis
used to apply liquids as sprajs However,
they arc not micrchangcablc m usage
Atomizers are designed to form relatively
coarse sprajs for application to the nasal
passages, the throat and the pharjnx, while
nebulizers emit fine sprajs v^hich reach the
larjfix and even the alveoli of the lungs Con-
struction characteristics and prmciples under
Ijing their operation and use have been re-
viewed See Chapter 8 (Aerosols) for
a discussion of this subject.
Atomizers. AH atomizers function accord
mg to the same basic plan Liquid placed in
a bottle is forced up and out through a dip
tube by amngmg for the pressure on the sur-
face of the liquid to be greater than that m
the tube As the liquid emerges from the dip
ionizers, Nebulizers, Insufflators 435
Fig 151 (.Top) Vacuum type atooiizer The air stream is pumped through the air tube
and does not enter the container In order to show the air tube, the larger concentric tube
through which the liquid flows has been unscrewed from the atomizer on the left the one
on the right has been sectioned Atomization takes place at the tip where the air stream and
the hquid meet A. air tube (metal), B vent C distal end of air tube D, canal for liquid
E, proximal end of air tube (Bottom) Pressure type atomizer (Le/l) In the sectioned
atomizer the path followed by the air stream has been outlined with a light color The
course of the liquid is indicated by arrows (Right) The Up has been unscrewed from the
atomizer in order to show the end of the small plastic or hard rubber tube through which
the liquid is forced The air stream passes through the larger tube F, atomizing chamber
G, tube for liquid H dip tube, I, removable lip
tube It IS dispersed mto a spray by force- stream is conducted at high velocity over the
able impact with a rapidly flowmg stream of exit end of the dip tube Pressure in the tube
air The two basic atomizers, the vacuum and is thereby reduced m accord with Bernoulli’s
the pressure ^pes, differ m the way m which pnociple'**^ and, as a result, liquid is pushed
the pressure on the surface is generated. In up mto the tube by the force of atmospbenc
the vacuum ^pe (Fig ISl, top), the air pressure Outside air enters the bottle
436 fresctiplion Accessonet ond Related Items
Table S9 Atomizer Solutioss
Compatible with Metals
Furacm Naul (Eaton)
Epbcdnoc Inhalant
Cepacol (Mcrrcll)
Vonednne (Mcrrcll)
Gluco-Fcdnn (Parle Davis)
Chlorctone Inhalant (Parke, Davis)
S T 37 solution (Merck Sharp & Dohroe)
through a small vent hole in the cap In ibe
pressure tjpc (Fig 151, bottom), part of
the air stream is detoured through the con-
tainer so as to reinforce the vacuum action
by an additional pressure on the liquid sur-
face The container is not vented os this
uould negate the pressure cffccL In atomizers
for home use. the air stream is generated by
squeezing a volved rubber bulb, those used
in ph)sicians' offices or m hospitals arc often
operated from a motorued aw compressor
Vacuum tjpe atomizers have narrow air
tubes and wide fluid tubes which result in the
formation of large volumes of coarse spray
On the other hand, pressure atomizers, which
arc designed with wide air tubes and narrow
Huid lubes, emit small volumes of a fine
spray Spfa)s from vacuum atomizers arc
intermittent, (he flow stopping immediately
on release of the bulb Pressure atomizers
tend to produce a more continuous spray
The usual nose and throat formulations
contaming sympathomimetic amines, anti-
septics, antihistamines and local ancsthcucs
may be applied more clicctivciy from at-
omizers since sprajs can reach throat and
nasal surfaces which gargles and mstiUations
from medicine droppers cannot.®* The phar-
macist probably should suggest the use of
atomizers more frequently than he docs His
clients will need advice in sclectmg from
among the several styles the one suitable for
the intended use For example, certain at-
omizers arc made with metal caps and out-
let tubes because these arc not easily broken
and may be stcnlizcd by flame or boding.
Unfortunately, many commonly used solu-
tions either attack metal or deteriorate more
rapidly m its presence Commeraal prepara-
tions compatible wiili metal atomizers arc
(istcd in Table 89 Atomizers designed so
that the solutions contact only glass, plastic
or hard rubber arc more fragile and can be
stcnlizcd only by tlic relatively mefliaent
method of immersion m alcohol or other
gcnnicidal solutions Some vacuum atomizers
nave twin outlet tubes and an adjustable
spray up which is convenient for dirccung
the spray back of the soft palate Tlicsc arc
parucularly suitable for oleaginous* and
viscous liquids Others with single lubes
(Fig 151, /op) ore easier to dean out if
clogged and arc reconmicndcd for solutions
which tend to crystallize Pressure atomizers
generally produce a finer spray which car-
ncs the medication mto deeper cavities of
the nose and the throat more readily than
docs the coarser spray from the vacuum
types A pocket-type atomizer operating on
the vacuum principle produces a very fine
mist almost equivalent to that from the
nebulizer which it resembles m design This
compact and capped atomizer is convenient
to cany, and, also, it operates with small
volumes of soluuon — an advantage when the
medication is potent and expensive
Before spraying medication into the nose
the patient should clear the nasal passages
by blowing The head is tilted back, and (he
aiomizcr up is placed iq one nostril, leaving
the other open Some atomizers have a nasd
guard winch fits over the spray up The
guard minimizes the danger of scratching the
luiing of the nazes and limits back flow by
prually plugging the nasal openmg Grooves
on the surface prevent buildup of air pressure
within the nasal caviUcs For throat applica-
Uons the nasal guard is removed and the
tube of the atomizer is placed m the mouth
With the Up directed toward the area to be
sprayed Atomizers tend to clog and are
most easily opened up with the help of a
fine wire such as a hypodermic needle wire
Plastic spray bottles arc commonly used
(or commercially available nasal and throat
mcdicauoos When the flexible container is
squeezed, the air inside is compressed and
the increased pressure forces the fluid up a
narrow bore tube into a small hole in the
* Oily vehicles are in Uiifavor because oil w^cr
feres with eJury activity of mucous membranes
Uhl there u a ml of lipoiU pneumonia if the tlrop-
lets ue intialcsL
Atomizers, Nebulizers, Insufflators
437
Up at the same time that a stream of air is
being forced into the tip through two tmy
holes The shearmg forces and the vacuum
effect are similar to those already described
for atomizers Patrons sometimes complain
that the bottle is not full, smce they fail to
realize the air space is essential to the for-
maUon of the spray Empty plastic containers
are marketed for use with extemporaneous
nasal preparauons
Nebulizers (Fig 152) consist of a small
vacuum-type atomizing umt enclosed m a
larger contamer or flask. The spray is formed
by nishmg a fine jet of air over the up of a
capillary dip tube It is earned forward by
the air current which, however, spreads out
and slows up because the flask chamber is
large and the outlet tube is wide Conse-
quently, only the smallest drops are canted
through the outlet tube, larger ones striking
the sides of the flask and falling back to the
base of the dip tube In some styles, this
baffling action is enhanced by curving (Fig
152, left) or oflfsettmg the outlet tube In
some (Fig 152, right) the spray is made to
strike against a baffle plate placed about 2
mm &om its pomt of ongin This more
efficient design^^’ facihtates subdivision mto
finer particles and elimmauoa of the large
drops Nebulizers are generally used with the
vent hole open, closmg it decreases the
amount of spray which is formed Nebulizers
are made only of glass or of plastics, since
metals accelerate deterioraUon of agents com-
monly used m aerosols Pocket-size models
are available Rubber bulbs are used to oper-
ate hand models Small compressors or tanks
of compressed oxygen, hehum or other gases
may be used m physicians' offices or m hos-
pitals
The nust or fog which flows out of the
nebulizer is a suspension of a hquid in air
and is classified as an aerosol Nebulizers
were first developed to apply bronchodilators
directly to the lungs to palliate chronic
bronchial asthma, chrome pulmonary em-
ph)sema and related conditions Along with
the local topical effect, there may be a pro-
nounced systemic acUon, smce these drugs
may pass rapidly mto the cuculatory sys-
tem.*^* Antibiotics and mucolytics which are
also applied to the lungs as aerosols prob-
Fig 152 Nebulizers (Top. left) The
nebulizer is used m the vertical position
shown A outlet tube, B, vent stopper,
C, air jet, D, capiUaiy dip tube, E, ap-
proximate limits of liquid chamber (Top
nght) Nebulizer to be held in a honzont^
posibon, thus, the base of the dip tube will
extend into the liquid m the chamber
F, vent stopper; G, air jet, H, baffle,
I, dip tube (Bottom) Nebulizing umt
with baffle-plate J, baffle plate, K, capil-
lary dip tube, L, air jet tube.
438
Pretcnption Accetiones ond Related Items
ably exert largely local action although some
ab^rption of antibiotics can be shown to
occur Partidc-sizc distnbution, which de-
pends on the design of the nebulizer and the
way in which it is used, largely governs where
the medication will unpingc, how much will
be retained or will be exhaled and, also, the
degree of absorption into the bloodstream
Particles of 3 micra radius and larger arc
taken out completely by the trachea, the
bronchi, the bronchioles and the alveolar
ducts Particles of 1 micron or more reach
the alveoli and 97 per cent are retained, only
3 per cent bemg exhaled Smaller particles,
0 3 to 0 4 micra radius penetrate to the
alveoli also, but 6S to 70 per cent of them
arc recovered on exhalation Nebulizers
should be constructed with suitable baOlcs
to remove the large panicles and to ensure
delivery of small particles, most of which are
the size optimum for deposition only m the
bronchioles, the alveolar ducts and the al-
vcolt Paruclc radu ranging from 0 S to 2 0
or 3 0 micra arc suitable
Publubed performance data for commer-
cially available nebulizers are scanty and arc
not in good agreement, perhaps due to dif-
ferences m cxpcnmental teeWes and to
vonations in the mdiv idual nebulizers used
Most mvcstigators have used the Vaponefnn*
and the DcVilbissf No 40 nebulizers and
have considered them to be satisfactory and
about equivalent with respect to the average
particle size produced. Of the particles pro-
duced by these nebulizers, 80 to 90 per cent
were found to be 1 S micra radu or less ' ”
Rcif and Holcomb‘S* have listed relevant
operating characteristics of nebulizers and
have studied the cfTccts of varying several of
these In view of the numerous claims for
supenonty of one design over another, it is
unfortunate that a systematic comparison of
all the available models and styles has not
been made
The pharmacist will have frequent contact
with chronic asthmatics who regularly use
aerosols of bronchodilator substances. He
may be asked to advise m the selection and
the preservation of the medication Epmepb-
nne fohalauon a 1 100 aqueous
soluuon of Icvo cpmcphrme bydrocluoride,
IS the standard preparation Propnetary solu-
* Tbs Vapooetna Company New York, N Y
t Tbs DsVilbua Company, Somenet, Pa.
Uonst containing 2 25 per cent of the racemic
form are staled to be equally cfTcctivc and
more stable, but advantages over the
ofGcial solution do not seem to be marked
Instability of cpmcphrme solutions is de-
lated by development of a pink color which
Incomes dark, brown and by precipitation
Exposure to sunlight and elevated tempera-
ture and opening the contamcr all accelerate
decomposition Although the pharma-
cist should not dispense a deteriorated prod-
u^. It has been shown that colored solutions
may not have decreased significantly m
potency Many asthmatics continue to use
even deeply colored or precipitated solutions,
provided that relief is still obtained Other
bronchodilator inhalant solutions, available
on prcscnpiion only, are isopropylartcrcnol
hydrochloride! (1 100 or 1 200) andproto-
kylol hydrochlondcll (1 100) Pressurized
containers of broochodilators are discussed
elsewhere (sec Aerosols, Chap 8)
Dtrccuoos for using nebulizers are given
on nebulizer boxes and inserts supplied with
the medications used The solution is added
by dropper through the throat tube, 10 to
20 drops being used The fluid level must be
kept below the Up of the dtp tube or atomiza*
uon will not occur Generally, the patient is
directed to place the nozzle just inside the
partially opened mouth, then to squeeze the
bulb vigorously once or twice, inhaling deeply
through the mouth with each compression
The vent is opened for maximum aerosol de-
livery The mholaUon of mcdicaUon may be
repeated several umes at intervals of 1 or 2
minutes until relief is obtained Swallowing
of the solution should be avoided so as to
limit systemic effects Gargling with warm
water relieves the dryness that sometimes is
felt Patients should be told not to be con-
cerned about the pmk color which appears
m the sputum as the drug is decomposed.
Excess soluUon should be left in the nebulizer
(capped) and not returned to the bottle
where u could hasten detenorauon of the
t VapoDtrna Inhalant Soluuon Vaponctna Co.
New York, Urcaiheaty Inhalant Soluuon Pucai
Co Inc.. &aitle, Aiiiunaoefnn Inhalant Solution,
Tlia)er Labs.. lov. New York.
I Uuprel iI>drochlonJe Soluuon, Winthrop
LabL. New York.
]|Ca)Uae Inhalation, Lakcsule Labt. Inc., htil
wa^ce.
Atomizers, Nebulizers, Insufflators 439
Fio 153 {Top) Powder insufflator Air (arrow) is forced into the bottle through a tube
(B) ending well above the surface of the powder The spray is forced up through the exit
hole m the cap and passes out through the exit canal (A) The lumens of the air tube and
the spray tube are painted a light color in the sectioned insufflator on the right {Bottom
left) Pocket type powder blower In this disassembled blower the parts are (upper left to
lower ngbt) bulb and air ]et tube, baffle, chamber cap The baffle slips down over the
jet tip au* dnected into it is deflected back against a micronizcd powder contained m the
chamber so as to whip it up into a cloud of f^e particles which floats out of the exit tube
{Bottom right) Abbott Aerohaler The arrows show the path followed by the ball when the
user inhales through the mouthpiece (C) Sifter caitndge (D) A spare caitndge is also
pictured
whole amount The nebulizer should be and the almost mstantaneous relaxation of
cleaned at least weekly Rmsmg with cool bronchospasm obtamed. Some asthmatics be-
water is generally adequate for plastic nebu- come psychologically addicted to the nebu*
hzers, hot water damages them Vmegar or lizer and pamc if they are without it or the
rubbmg alcohol may be used for glass nebu- medication even temporarily Others take the
hzers It IS sometimes necessary to undog medication too frequently and m excess,
the jets with a fine wire thereby producing anxiety states and fast-
Pngal>*^ has pomted out the mixed bless ness to the drug. The pharmacist should
mgs of the ease of aerosol administraboa understand why &ese clients may sometunes
440 Preicnphon Acceisories ond Relafed Items
E
Fta 154 Hjpodcmiic sjnngcs (Le/i)
S)r]n£c ^vhlcb has plunger and barrel
ground to tit together A, plunger n, bar*
nd flange C, plunger guard. D, barrel.
£, tapered Lucr up (Rishi) Interchange-
able type The syringe has both metric and
apothecary graduations it also has a Lucr
LoV tip (F)
become quite querulous Some lascstiga-
tors'* ““ hate reported that syslcrmc effects
from inhalation of nebulae of sympatho-
mimetic amines are quite limited and base
considered this to be cv idencc that only minor
quantities arc absorbed Others’** do not
agree Although asthmatic patients uith car-
dmvascular msolvcrocnts or diabetes shotsed
no ill effects from inhalation of cpmephnne
solutions," federal regulations r^uire that
sy'mpathomimctics be labeled to mdicate that
they should not be used if high blood pres-
sure, heart disease, diabetes or thyroid disease
IS present unless directed by a physician
Powder insufllalors or blowers arc used to
mix finely divided solid particles with air to
form a spray for topic^ application One
form IS shown m lugurc 153 {top) Air from
the compressed bulb whirls up fine powder
in the reservoir formmg a cloud which is ear-
ned out through the outlet lube This can be
deposited as a uniform thin layer of powder
on nose, throat, car, tooth socket or body
surfaces Powder blowers should be dispensed
as accessories much more frequently than is
customary m current practice
Finely divided or micronizcd powders are
sometimes inhaled orally or nasally to pro-
duce topical and systemic effects akin to those
produced by liquid aerosols Inhaled dusts
have been found to be imtating,*’ and the
vo^e for this therapy has passed taking with
It most of the spcci^ized devices that were
designed for it The Acrohalcr used for ap-
plying tsopropylaricrcool sulfate* u tllus-
trated (Fig \Si, bottom, right) A sifter car-
tridge of powdered drug is inserted m the
assembled Acrohalcr When the user inhales
through the mouthpiece or the noscpiece, a
loosely rolling ball is pulled upward and for-
ward, rapping against the cartridge so as to
shake out some of the powder through two
small holes m the cartndge plug. The dust is
then inhaled A pocket type powder blower
for applying micronizcd powders to both
upper and lower respiratory tracts is available
(Fig 153, horrom, fe/r) For proper acuon,
powder insufflators and the powden them-
selves must be kept dry to prevent clump-
ing and clogging
HYPODERMIC SYRINGES AND
NEEDLES
A synngc is an instrument used to inject
liquids into the body or to instill them mto
b(wy cavities ** Bulb syTuigcs and gravity-
flow (fountain) types arc described with pre-
senpuon accessories made of rubber The
forms and the uses of the plunger or hypo-
dermic syringe arc also of significant imj^rt
to the pharmocut
• Sonuxlnne Sulfate, 10^* and 25'*. Abboll
Laboratone*. North Chicago, (Iliooii.
Hypodermic Syringes and Needles 441
Because of the capacity for misuse inher-
ent m instruments which are capable of m-
jecung potent materials into the body, phar-
macists clearly bear a great responsibili^ m
their control of the distribution of hypodermic
syringes and needles to lay and professional
people Federal regulation is lacking, but a
number of states have laws which designate
by whom and to whom they may be sold For
example, in California they may be dispensed
only by registrants A prescription is re
quired unless the item is supphed to another
professional person or dispensed for admims-
tenng msulm to a diabetic or epinephrine to
an asthmatic Of course, the pharmacist is
morally bound to ensure as far as possible
the legitimacy of sales without prescription
Diversion of these articles mto illicit use with
narcotics is the prmcipal danger
Descnption of Syringe. Basically, the hy-
odenmc syrmge (Fig 154) consists of a
arrel and a plunger, both of which are usu
ally made of a borosilicate glass resistant to
thermal shock and low in alkalinity The all-
glass syrmge is known as the Luer syringe,
after its mventor The barrel is a tube open
at one end and closed at the other except for
a hollow tip The open end is thickened and
extended radially outward to form a Sange
to prevent shpping of the barrel through the
hngeis The plunger is a glass rod with a flat
distal end and a proximal end shaped mto a
button type knob The relative duneosions
of the barrel and the plunger for a given
syrmge are such that the plunger will move
freely throughout the barrel, yet the surfaces
of the plunger and barrel must so closely ap-
proximate each other that fluid cannot pass
between them even when under considerable
pressure Suitable fit has been achieved in
two ways In one, both the barrel inner sur-
face and the plunger outer surface are ground
with abrasives, then the two parts are placed
together and further ground to make a match-
mg pair The two components are marked
with identical serial numbers and must al-
ways be used only together smcc they arc
uniquely fitted If one part is lost or broken,
the other must be ducarded The second
method makes use of unground barzels made
of a glass tubmg which has so uniform and
constant an mtemal diameter that plungers
can be precision ground to given dimensions
to fit It Consequently, both barrels and plung-
ers are mterchangeable * Broken components
can be replaced without difficulty because of
this standardization Syrmges are usually sup-
plied with a spring metal retaining clip which
presses gently against the plunger so as to
keep it from accidentally slippmg out of the
barrel Users often prefer to remove this
plunger guard, since it tends to mterfere with
manipulation of the syringe
The tip of the syringe barrel provides the
point of attachment for a hollow steel needle,
the part of the instrument designed to pene-
trate into the body The tip may be glass
with the exterior surface ground, or it may
be formed from a metal cyhnder welded to
the glass The usual Luer metal or glass tip
has a taper with standardized dimensions,!
which allows the needle hub to be shpped
over It and to be held on by friction When
this method of holding is used, the needle is
reasonably secure, but it may slip oS if it is
not properly seated or if there is need for
much manipulation of the needle after m-
sertion A more positive gnp is assured with
(he Luer Lok tip t This is a patented metal
collar (Fig 154) with a circular mtemal
groove mto which a flange on the needle hub
may be mserted A half turn locks the needle
m place The syrmge tip is usually concentric
to the barrel axis, but syrmges with eccentric
tips are avaJable for situations (as m mtra-
venous work) where it may be desirable to
mtroduce the needle as nearly parallel to the
surface as possible
S^Tinge Graduations. Tlie range of ca-
pacities for general purpose syrmges is from
2 to 100 ml , larger and smaller ones are
available for specialized uses All markings
on the syrmge, mcluding graduation lines and
numerals, should be apphed with pigments
capable of withstanding repeated autoclaving
They may be fused m, fused on or etched and
fused Si^cs (Fig 154) may be double (m
minims as well as ml and fractions thereof),
* Multifil Synoge, Becton Dickinson and Com
pany, Rutherford, N J
tAmencao Standard Dimensions of Glass and
Metal Luer Tapers for Medical Appheauons, ASA,
Z70 1 ]9d5, American Standards AssociaUon, Inc ,
New York.
t Becton, Dickinson and Company, Rutherford
N J
4-42 Pretaiplfon Accessories and Related Items
Fio 155 <Le/i) Tuberculin s>ting» Disposable s)'nsse. Each syringe has tv>o scales^
one graduated to 0 01 cc. umts, and one to miotm units The plungers are colored blue
(Centtr) Insulm s)nflge4 The plungers have been pulled back to tbe mark for 30 units of
U SO iiuulin Short i}pe U 80 syringe short type double-scale synnge long type U 80
syringe with blue plunger disposable U 80 plastic synnge (Right) The Bushcr Automatic
Injector The injector at the left u loaded with a syringe and has been cocked so that touch
mg the lever will move the sy nnge ahead and inject the needle.
or single (metne only) or may be spcaoltzcd
Tuo basic factors ailcct the acoura^ of
synnge dosage ” One is (he built m accuracy
of the synnge and the other is the accuracy
of the admmtstration Federal speciScatioos*
which arc generally followed by the industry
require synnges to be tested (with water) for
accuracy at each mam graduation mark with
a calibrated burette Syringes must dchscr
:h 5 per cent of the capacity mdicated at each
marL Each conventional ground-glass synnge
must be mdividually graduated, since mtcr>
na] diameters of the barrels vary unpredict-
ably Prccuion sizing of tubing used for
*CG-5-921b Federal SpeciAcaiioa, Syringe
Luer (All glass) August 7 1958 General Services
Admimstrauon Regional OtIIcet Federal Supply
Service New Yoik, San Francisco and elscwvre
No charge.
tcrchangcable synnges allows graduation cn
masse To facilitate accurate readings, tbe
plunger may be made of colored ^ass (usu
ally blue) or it may have a narrow black or
colored precision line near the bottom It is
esumated” that most of the available glass
synnges are accurate to ri: 3 per cent Phar-
macists tend to overlook the possibility of
using hypodermic synnges to measure small
volumes when compoundmg
Special purpose synnges (Fig 155) are
named according to the usual intended use
These mclude the vaccine,” the ‘luberculm”
and the “insulin’ syrmges. They may differ
from usual sytingcs m scale graduations, m
over oil capaaty and, perhaps, m length rela-
tive to capacity A typical vaccine synnge
may have a capaaty of 1 ml with graduations
to 0 05 ml. It IS mtended for use aUo with
Hypodermic Syringes and Needles 443
Fia 156 Disposable
synnges (Across) Clear
polystyrene barrel with
removable needle tram
lucent polyethylene bar
rel needle not supphed
glass barrel needle per
manentlyattacbed poly
styrene syringe supplied
with medication (peni
cillm suspension) and
a separately packaged
needle tramlucent bar
rel supplied with medi
cation in glass container
The needle guard is used
also as the piston when
the syringe is assembled
for use (Top) Metal
barrel and piston with
rubber sealed glass car
tndge containing medi
cation
epmephrme and other medications for which
doses are 1 ml or less Tuberculm synnges
are 0 25, 0 S or 1 0 ml m capaci^ and have
long barrels with narrow mtemal diameters
to allow precision m graduation to 0 01 ml
The thm plunger is colored blue typically
This design was developed for the mtra
cutaneous mjection of very small doses of
tuberculins for diagnostic purposes insulm
synnges are shown m Figure 155, center
Disposable Syringes Sterile synnges which
are to be discarded after being used once
have advantages that have led to their ac
ceptance m some quarters These disposable
synnges are conveiuent to use and lessen
hazanis of cross infection Institutions tend
to convert to usmg them if cost studies show
that the change is justified by savings result
mg from freeing personnel equipment and
space needed to clean sterilize, assemble and
store reusable synnges ** Individual phy
sicians choose to cany them m their bags
on the basis of convemence Disposable
synnges are made of glass or plastic or
Iwtb Some have metal parts also The plas
tics used mclude polys^rene, polyethylene
polymethylmethaciylate, polypropylene and
nylon Polystyrene (possibly the most
used) and polymethylmethacrylate are glass
like m appearance, while the others lack opti
cal clanty but are more flexible A major
deterrent to a wholehearted acceptance of
plastic synnges has been the demonstration
that, contrary to ongmal expectations, plas*
tics have been shown to be mcompatible with
a number of medications “ Users also
have been disenchanted on occasion by
poorly made synnges which were difficult to
assemble or faul^ in operation owing to ill
fit of barrels and plungers or to loose needles
Disposable synnges are marketed in a
vanety of designs (Fig 156) Some resemble
conventional synnges m appearance and are
supphed m an assembled form ready for use
444
Prescriplion Accettones and Reloled Hems
Fio 157 {LtU) H)poiIiniiic needle* These arc the same length, since the shaft of the
security bead needle (fe/r) u measured from the bead A, shaft, B secunty bead. C, hub,
D gauge number (/fig/ir) Variations m hypodermic needle points (Top) Underside siews
{Bottom) Side sicsss {Across) Short betel regular point, long bevel regular point, Huber
point In the side views the points are turned so that the openings into the canals face toward
the nghL
in individual sterilized paper envelopes or
polyethylene bags These may be oU plastic
or they may have a glass barrel with a plastic
plunger They are available with or without
needles Needles, when attached, are usually
covered by a separate plastic sleeve Some
forms of single use units arc supplied only
with a cartridge of on mjectablc agent con*
tamed within ibe synngc barrel A synnge of
this type has to be taken apart and reassem-
bled in order to insert the shaft of the piston
mto a rubber plunger The cartndges have
Hypodermic Syringes and Needles 445
Table 90 Suggested Needle Sees
Length
Injection
Gauge
(inches)
Bevel
Examples
Intradermal
26G
V4 orH
V s b
Schick, Dick, allergic tests
Subcutaneous
26G
Vi
r b
Insulin, immunizations
25G
Vito%
r b
22G
IVi
r b
Hypodermoclysis
Intramuscular
24G
% or 1
r b
Polio vaccine
23G
22G
1
1
r b
r b
Hormones, bismuth
22G
m orlVi
r b
Penicillin
20G
IVi
r b
Intravenous
22G
morIVi
s b
Penicillins, transfusions
20G
1V4
s b
Glucose, blood tests
r b , regular (long) bevel s b short bevel v $ b very short bevel
attached needles and are usually made of
glass so that contact with the plastic of the
synnge is avoided In yet another type of dis
posable product, a rubber sealed glass car-
tndge with a selected stenle medication and
neede is provided for insertion into a re-
usable metal synngelike device Several other
fonns have been marketed and new ones are
undergomg tnal
Dispeosmg of Sjnngcs. Syrmges are sup-
plied m individual boxes or, for large users
such as hospitals, m bulk packages The
commumty pharmacist is well advised to m-
spect each synnge before he releases it to
his client, smcc these easily broken instru-
ments are sometimes unjustiGably returned
as having been defective when purchased
Proper fit of syringe components can be
tested by covering the Up hole with a finger
and pullmg back on the plunger The vacuum
created should be sufficient to make movmg
of the plunger difficult Before the plunger
IS released the vacuum should be broken by
uncovermg the Up hole, otherwise, the
plunger may shoot back to its miUal posiUon
with sufficient force to knock out the bottom
of the barrel
Hypodermic Needle ConslrucUoo. The
parts of the hypodermic needle are illus-
trated m Figure 157 Needles are made firom
vanous special steels which arc chosen to be
strong, flexible and rustless or nearly so
Needle size is designated by two numbers,
the gauge and the shaft length in inches
Gauge numbers represent the outside diam-
eter of the shaft expressed according to the
Stubb s English wire gauge system They run
from 27, the finest, to 13, the thickest The
shaft or cannula is measured from its junc-
ture with the hub to the up of the pomu
As an excepUoD, the “security’ needle is
measured from the small metal bead which
IS fastened 14 inch from the hub (for easy
withdrawal in case of accidental breakage)
Lengths range from mch up to 3V4 mches
The gauge number is often stamped on the
needle hub, the length is not
SeUebon of Needle. The choice of needle
size for a given use is governed by factors
such as the desired depth of penetration, the
fluidity of the injecuon and the safety and
the comfort of the patient, Fme needles may
be suitable for thin mobile liquids, while
thicker ones may be needed for oils or sus-
pensions Short needles may be adequate for
thm persons, while longer shafts will be
needed for similar mjecuons into obese pa-
Uents Table 90 presents suggesUons for
needle sizes to be used for several common
types of mjecuons It should be reco^uzed
that physicians or nurses or pauents may
express mdividual preferences on occasion.
Specialized needles for parucular uses such
as tissue biopsy or spmal, hemorrhoidal or
tonsdar mjecuons arc not usually stocked by
the commumty pharmacist This is also true
for needles with gold or silver cannulae
446
Prewiplion Accessories and Relared Items
1
Fig 158 Disposable needles (LtfO
The needle in the pacLage is sealed under
a slifl plastic film (/?ig/ii) The opaque
plastic tube u opened by removing lU
cap {Center) Two unpackaged needles
(/e/I) with plastic hub. (ng/ii) with metal
hub
Several designs for needle points have been
developed (iMg 157, rig/ii) All arc tapered
with front and side bevels to nuntmize the
amount of force needed for mscruon and to
reduce pain and trauma.** Needles with the
regular long front bevel arc generally used
for hypodermoclysis and subcutaneous and
intramuscular injections Those with short
bevels arc preferred for intravenous injccuons
and transfusions Needles with a very short
bevel arc used intradcrmall) As it is being
inserted, the regular point someumes punches
out a plug of tissue which may occlude the
cannulx Because of its dosed front bevel
which places the opening parallel to the shaft,
the Huber point (Fig 157, ng/ir) pierces
rather than punches Most users do not seem
to discriminate m favor of either regular or
Huber potnts
Needle Sources, Paclaging. Needles ob-
tomed from reliable sources in the United
States vary little m quality A number of sim>
pie but ctlcctive quality tests which the pbar*
macui can apply without elaborate equip-
ment have Ncca described** N'ccdlcs arc
supplied to the cximmunity pharmacy in boxes
of 12 of the same sue or, less frequently, of
lusorted sizes Hospital packs may be gross
lots To protect the points, the needles may
be encased in small plastic tubes or else
mounted on thm cardboard
Needle »ucs. A needle wire is a thin stam-
less steel rod of such diameter and length
that it may be fitted through the hub into the
cannub and extend for a short distance
beyond the pomt These wires are useful in
protecting needle points and m preventing
clogging of cannulac when the needles are
not in use For example, diabetics will find
that prior insertion of needle wires will re-
duce the madcnce of bent points m needles
stcnlizcd in a pan of boiling water Wires
may be supplied m the boxes of needles or
may be obtained separately The pharmacist
should supply a wire with each needle and
should explain its function
Disposable Needles. It is difficult to mam*
tarn sharp pomts on needles vvhen they arc
reused several times Grinding them on
smooth oil stones (Arkansas stones) will
restore bevels and remove burrs or fishhooks,
but this requires considerable skill Smee dull
pomts make for painful injections, stenle dis>
posable needles (Fig 158) have been de-
veloped One time use of these needles not
only elimmatcs problems of sharpening but
also docs away with costly, time-consuming
cleaning and sterilization procedures and w-ith
transmission of scrum hepatitis Since rc-
usabili^ IS not a factor, disposable needles
can be made of less expensive steels Plasuc
hubs which cannot be boiled or autoebved
may be used Packages arc designed to raam-
tam sicnlity and to permit the needles to be
removed without contommaijon Cbst-studics
m hospitals appear to justify use of dispos-
able needles in place of reusable ones
Use and Mainlcnonce of Syringes and
Needles. Pharmacists should be able to an-
swer questions about the use and the care
of hypodermic syTtnges, needles and related
Items Although the pharmacist docs not in-
ject drugs, be should be suffiacntJy mformed
about all parenteral technics to answer ques-
tions about hypodermic devices used m them.
Reviews” *” of common technics should be
utilized. Care and handling of syringes has
Hypodermic Syringes and Needles 447
been well-descnbed and published m a fonn* herent surfaces, but may damage the glass
convement to distnbute to users Immedi- Boilmgfor lOmmutes ma25 per cent aque-
ately after use the synnge and the attached ous solution of glycerin is said to be effective
needle should be flushed several times with if the parts are separated while still hot.^* As
cool water The disassembled components a service to his clientele, the pharmacist may
should be soaked in mild detergent solution wish to equip himself with a synnge opener
for 15 to 90 min utes, the longer times being This is an ^-metal synnget with a female
advocated if oily medications are to be re- Luer-Lok tip In use, the syrmge opener is
moved. Prolonged soakmg or the use of a filled with warm water or cleaning solution
cleanmg solution that is alkaUne, concen- and attached to the tip of the stuck syrmge
trated or hot may remove the pigment or Steaddy mcreasmg pressure is applied until
destroy fit of plunger and barrel After nns the stuck plunger is expelled from the barrel
mg, the synnge and the needle may be Stains and deposits which develop on
sterilized by one of the several standard syrmgcs may be removed by swabbmg with
te chni cs cotton moistened with an appropnate reagent.
If syrmges and needles are not rmsed and Alkali deposits and blood are removed with
disassembled immediately as suggested, the 10 per cent mtnc acid, iron stams by 10 per
parts later may be found to be stuck to- cent hydrochlonc acid Concentrated am-
gether Soabng overnight or longer m a de monia, sodium citrate soluuon, alcohol and
tergeot solution frequently releases the ad orgamc solvents are sometimes used suc-
• Glass synnges recommended, care and ban cessfuUy
dlmg, Leaflet supplied by Becton Dickinson and t Becton Dickinson and Company Rutherford
Company, Rutherford N J N J
Pfescriplion Accetiories ond Related llemt
4ia
Jct'tnjccfon. Numerous attempts'^ ha\e
been mode to dcselop mjcction devices su*
penor to the h}podennic s)nnge and needle
Prominent among these have been mstru*
ments intended to force a Cnc ]Ct of medt>
cation under high pressure throu^ the dermis
mto the tissues While the basic pnnctplc
seems to be sound, difCculues in design have
dela)cd production A smgle-dose mjcctor is
not )ct on the matket, W a gun-shaped
multidosc jet injector (Fig 159) is currently
available • Dcpcricncc~ with large groups
mdicates several advantages of the jet injec-
tor for mass inoculation uithvaccmes These
include relatively Tess pain, less time required
per injection decreased personnel needs, re-
lease from need to stenlize between mjcctions
and lower cost per injection A rate of 1,000
to 1,800 shots an hour may be obtained
Virus of scrum hepatitis cannot be trans
nutted It IS stated that viscous oQ suspen
sions and particulate suspensions can be
injected ** ’rtcrc may be a greater madcncc
of bleeding, erythema and transient local
edema than from needle punctures Cutting
of the epidermis may occur if the jet is per-
mitted to move about during mjcctioo
Mechanical ddTiculucs may occur •••
An electrically driven hydraulic pump con-
nected to the gun by a flexible hose forces
fluid under pressure into the gun handle This
cocks a sprmg which, when released by pull-
ing the trigger, pushes a plunger forward to
eject the dose of medication through a line
jet (less than 0 006 inch diameter) m the
injector head The medication is supplied
automatical!) from standard multiple dose
vials of 5 to 100 ml capacity It passes
through a closed s)stcm which can be re
moved from the gun for auioclavuig before
starting a senes of mjcctjotis Injeciion vol-
ume may be varied from 0 1 to 1 0 ml by
choosing the plunger of correct length A
dosage indicator is provided on the side of
the injector gun A different nozzle is used
for subcutaneous mjeaions and intramuscu-
lar injections lotxa^rmal injections may be
made with an adapter, but intravenous in-
jections are not given by the jet method.
• Hypjtpray VfoJel 'K," R. P Svhaer Corp^
Ot iml Mwh.
While the high onginal cost may seem to be
a deterrent, the evident usefu^ess of this
device for mass moculation should encour-
age the pharmacist to brmg it to the attention
of local public health and school ofQcials and
phj-sioans The Hjpospray may be dispensed
only on prcscnption.
DIABETIC SUPPLIES
Diabetes is an incurable condition which
may demand rigorous attention to diet, con
unued medication and constant vigil to main-
tain life The pharmacist should lx prepared
to render cojnpJeJc and knowledgeable serv-
ice to the more than 3,500,000 diabetics m
this country
SjTingcs and Needles, The usual insulin
synnges (Fig I5S) have a capacity of 1 cc.,
but synnges able to hold 2 and 3 cc are
available also In order to facilitate the self-
admmisiraiion of insulin by the diabetic,
synnges are graduated in units of insulin
The pharmacist must be certain to dispense a
s)nngc commensurate with the strength of
insulin that his client is using The 40 unit
scale generally is red and the 80-uoit scale
IS green to correspond with the identifjing
colors specified for the boxes and the labels
of these strengths of insulin Dosage error is
less likely w ith a S) nngc having a single scale,
but a s)ncge with a double scale may be de-
sirable for sjTCCial cases Disposable syringes
(Fig 155) arc useful in cmcigcncies or while
traveling, but they ore too expensive for
routine daily use The sizes of needles used
for the subntancous injection of insulin arc
grtcB la Table 90 Either the regular pamt
with a long bevel or the Huber point u pre-
ferred.
Pocket kits containing syringes, needles
and various occcssoncs are available The
Bushcr Automatic Injcctorf is a spring de-
vice that can be set to insert the needle at
the proper angle and depth when a tugger is
rclcasco (Fig 155) It may be suggested as
an aid for children or timid adults
Sterilization technics practiced by diabetics
are quite simple The disassembled syruigc
and the wired needle are placed m a wire
strainer (the common household type) which
u then immersed m water and boiled for at
r Becioa DuLmtoa aaJ Com^i^y
Diabetic Urine Tests 449
least 10 mmutes The parts are assembled
after having been allowed to cool m the
strainer removed from the water Contamma-
tion IS avoided by holdmg the plunger by the
knob, the barrel by the sides and the needle
by the hub Many diabetics will sterilize
syrmges and needles as infrequently as once
a week, daily sterilization is certainly much
safer Immediately after use, the syrmge and
the needle should be rinsed with cool lap
water and then with a small amount of alco
hoi Between mjections the parts may be
stored m rubbing alcohol The practice of
relying on a simple nnsmg with alcohol as the
only routme means of preventing contamina-
tion IS to be discouraged
Special Accessories. The diabetic may be
concerned about the need to protect his in-
sulin against deterioration when be must
carry a supply with him while travelmg It is
evident that msulin loses potency so gradu-
ally at room temperature that there is no cause
to anticipate a significant change over the
short tune mterval during which a given vial
would be used up once started Especially
designed vacuum bottles which sup^rt an
msi^ vial m a packing of ice are of some
use for long trips
Diet Factors. In order to manage his con-
dition properly the diabetic frequently re-
quires special diet foods and diet informa-
tion, sugar free medication, diagnostic aids
and guidance The pharmacist should be pre-
pared to offer all of these The synthetic
sweeteners, saccharm and Sucaryl,* are avail
able m tablet, powder and hquid forms It has
been reported*** that some sugar free” gums
contam mgredients which are converted into
glucose by salivary enzymes Bauer and
Wasson** discussed the often overlooked
gljcogenetic properties of alcohol, glycerm
and propylene glycol Liquid medications'*
suitable for diabetics can be prepared by the
pharmacist as a distmctive mihvidual con-
tnbuuon to the welfare of his diabetic cli-
entele
DIABETIC URINE TESTS
The diabeuc is generally directed by his
physician rouunely to test for glucose m his
unne, since its appearance mdicates failure
* Sucary!, Abbott Laboratories Chicago HI
to control the condition Several well-estab-
lished methods depend on the reduction of
cupnc ions m alkaline solution to form a
reddish precipitate of cuprous oxide *** Bene-
dict’s test methodf requires a test solution,***
test tubes, medicine droppers and bottle
brushes which the pharmacist should be ready
to supply The Chmtestt tablet, a combma-
iton of cupnc sulfate, anhydrous sodium hy-
droxide, citnc acid and sodium bicarbonate,
IS more convenient to use and to carry along
when travelmg One tablet is added to a mix-
ture of 5 drops of unne and 10 drops of
water m a small test tube Boilmg occurs as
heat IS produced by the solvation of the so-
dium hydroxide and reaction with citnc acid
Tlie curate complexes with cupnc ion to pre-
vent precipitation of cupnc hydroxide Effer-
vescence occurs as the carbon dioxide formed
from the sodium bicarbonate bubbles through
the hquid Shaking the tube dunng the reac-
tion IS cootramdicated smee the ‘ blanket” of
carbon dioxide protects the system against
an interfering reacuon with atmospbenc oxy-
gen The tube is shaken gently at 25 seconds
after the boiling stops and the color is com
pared with a standardized color scale for
quantitation The tablets are very hygroscopic
because of the anhydrous sodium hydroxide
When detenorated, they are dark blue rather
than spotted bluish-white Containers should
be kept tightly sealed Because of its moisture
content, cotton should not be placed m the
bottle Sealed m foil tablets are available to
reduce spoilage A neatly constructed kit con-
taining tablets and the necessary apparatus
makes a compact umt to offer to the diabetic
The pharmacist should cauuon the user that,
due to their lye content, Clmitest tablets may
be injurious if handled or swallowed,*®^ and
they should be kept out of the reach of chil-
dren Dextroteslf is available for the quan-
titative delennmauon of blood sugar by the
chnictan In this procedure sulfosahcyhc acid
(m tablet form) is used to precipitate blood
t Place 8 drops of unne and 5 ml of reagent m
test tube Immerse in boiling water for 5 minutes
Observe when cool Reducing substances are pres
ent in increasing amounts as a green yellow-orange
or red preapitale is formed
t ^nes Company, Inc Elkhart Indiana.
§ Ames Company Inc
450 Prescnplion Acceuories ond Reloled llemi
proteins before the Omitcst tablet is rcactecL mfonnation (| The pharmacist must be ncU
TcS'Tapc* and Quustuf are enzyme* aware that seemingly minor infections such
impregnated paper strips which, when dipped as colds, boils and carbuncles rapidly be-
into unne samples, desclop a color if glucose come serious conditions m the diabetic.^*
IS presenL Topical reactions'* for the Tes- The need for extreme attention to foot b)-
Tape arc gieoe and the treatment of corns, calluses,
glucose oxidase
1 Glucose 4* Oa - ‘ — » gluconic acid H-Oa
peroxidase
2. HjOa -f o lolidine ■ > blue color (composition unknown)
The colors that are seen arc shades of green,
since a )eIIow d}e is also present in the
paper A new Qimstix (available m 1962)
utilizing similar cnz)'mcs but a diilcrcnt
chromophares}stemde\elops lavender colors
Color s^es are used for a rough quantita-
tion'* of the amount of glucose present It
IS worth noting that ascorbic acid dela}s the
color development, intcrfcnng amounts of
the vitamin may appear in the urine follow-
ing therapeutic dosages The impregnated
paper must be stored m tight, light-rcsistaot
coolainen and protected from heat to avoid
enz)‘me deterioration
Since kclonuru develops when fats are lo-
complculy mciaboliicd m poorly controlled
diabetes, the diabetic may be directed also
to examine his urme for ketone bodies The
reaction of sodium nitroprusside vviih ketones
(pnnapally acctoacctic acid) to produce a
dutmeuve purple color u the basis for the
commercially available Acctcsif reagent
tablets and for a test paper, the Ketostu
reagent stop ^ Smcc the unne also becomes
moderately acid, with the pH approaching
4 S, indicator papers such as the phenaph-
IhazineS paper arc used by diabetics to signal
approaching acidosis
Sfuch of the voluimnous dabctic btera-
turc'**** IS aimed at the diabetic himself, but
It IS also of mterest and value to (he phar-
macisL Manufacturers of diagnostic products
and medications for diabetics provide useful
* EU Lilly anJ Co lQJuiup>Ui. loUiaox
t Amci Cotnpaay, Inc
t SoJium DiiropnaviUc. diiodiuni pbavptiaie aaJ
tnuooaccUc aetd Amu Co^ lOv
f SoJiLRi iLmirophcovl-azo-iuphiboI d lulfoiuie.
Sitmiae paper, C. R. S<ju.bb U Sou, Sew Yoik,
N Y
blisters or athlete’s foot with mild but effec-
tive methods is occasioned by the character-
istically poor circulation of blood to the feet
SURGICAL DRESSINGS AND
RELATED SUPPLIES
Surgical dressings ore matcnals applied
over sores, wounds and other lesions They
have a long history of usage** These and
refated supplies are appropriately available
through the pharmacy to physicians and lay-
men Surgical supply bouses are the major
outlet for specialized items m this category,
such as surgical mstruments, sutures and bulk
packages of dressings In terms of retail
dollar value, nonpharmacy outlets such as
supermarkets and variety stores now sell
nearly 40 per cent of the first aid items pur-
chased by the general public ** *>* This is
evidence that pharmacists m general have
failed to demonstrate to tlic public a uiuquc
ability to advise m the selection and the use
of these items
Surgical dressings have multiple functions
Protection of wounds from bacterial or other
contammauon and from furtiier injury is a
prime one Uses which sometunes may as-
sume paramount importance ore the partial
or the complete immobilization of an injured
area, the support of damaged tissues, the
control of bleeding, the absorption of exuda-
tions and the holding of medication m place
These and other functions will be brougnt out
as vanous forms of dressmgs are discussed
Items referred to by brand name have been
II Amei Pictoclioic (a cooiiauias tcries of high
I to cuxreni disgnovis anJ therapy), CuJebook
tv a Qcw diabetic pauent (a booklet), Ames Com
pasjr. loc.
Surgical Dressings and Related Supplies 451
Fig. 160. {Left) Examples of cotton gauze mesb. {Top) Type VII, 20 x 12 mesh; Type I,
44 X 36 mesh. {Bottom) Type VIII, 14 x 10 mesb. {Right) gauze pads. The 2 mch x 2 uch
pad can be unfolded to a 2 mch x 6 mch rectao^e without exposmg loose ends.
selected only oa the basis of the authot^s
familiariQ' with them; no attempt has been
made to be all*inclusive.
Cotton is the major raw material from
which dressings are made. Rayon, cellulose,
plastics and a host of adjunctive agents are
also used. The production and the processing
of cotton for medicinal uses has been de-
scnbtd.®^ Cotton is naturally nonabsorbent
because it contains waxes, resins and fat^
substances which prevent water from wetting
it. It is made absorbent when these sul^
stances are removed by boiling the previ-
ously cleaned cotton for several hours jo
dilute sodium hydroxide solution under steam
pressure in a closed tank (kier). Subsequent
bleachmg with sodium hypochlorite converts
the cotton from its natural gray color to a
more appealmg white. Nonabsorbent cotton
has relatively limited medicmal uses as pad-
dings and as moisture-resistant backings for
dressings, for example. Absorbent cotton as
such and also woven into fabrics is the form
which is more widely used.
Official standards*®* for purified (absorb-
ent) cotton provide specifications for purity
and absorbency and impose other require-
ments as well. Cotton fibers are unceliular
cellulose hairs with a spiral twist that makes
them especially valuable for spinning. They
vary in length from a few millimeters up to
50 mm. or slightly more. Short-staple cotton
fibers average less than 25 mm. , medium-
staple fibers average less than 25 mm.,
medium-staple fibers average from 25 to 30
mm. and long fibers from 30 to 40 mm. Each
grade Is employed m some form of dressmg.
Small pieces of cotton have been found to
be so useful as swabs that machine-made
cotton balls have been marketed in three or
four sizes. They are used to wipe oS fluids,
exudations and medications and to apply
liquids, cleansers, antiseptics and medica-
tions. Similar balls made of rayon are said
to be softer, smoother, more lint-free and
more absorbent and to offer less hazard from
static electricity. Bulk packages containing
one Co several thousand nonstenle cotton or
rayon balls are supplied to institutions.
Smaller packages containmg sterile cotton
balls are stocked in pharmacies. These are
used mainly for cosmetic uses or for baby
care.
Cotton-tipped applicators also make useful
452
Preicnpfion Accestonet and Retofed Items
&v.abs for appl)!!)^ medications, cleaning
lA’Ounds, noses and cars and taking cultures
They arc made by winding long-fiber cotton
on the end of smooth birch sticks A bmder
which IS insoluble m alcohol and common
medications and not aiTcctcd by stenlizauon
may be used to hold the cotton on Appli-
cators may be 3 or 6 inches long, tips may
be small or large Bulk packages arc non-
slcnlc Small packages of slenle applicators
arc familiar first aid items m pharmacies
Short double-tipped stcnic applicators arc
marketed under scscral brand names for
home uses, especially for baby care These
should have flexible, nonsphnicnng steins
such as those made of rolled paper
Cotton Gauze. Absorbent gauze is cotton
m the form of a plain woven cloth conform-
ing to standards set forth in the US P It
IS an open meshw-ork of threads spun from
long-staple cotton fiben /Utcr the cloth is
woven, It IS rendered absorbent and bleached
by kicnng m processes smular to those used
m making surgical cotton Gauze is classified
into t>pcs according to its mesh Mesh is
denoted by two figures, the first being the
number of warp or lengthwise threads per
inch and the second the number of fill or
Lateral threads per inch There arc eight
ofiicial T)^^ I, the most closely
woven, has a 44 x 36 mesh, T}pc VIII has
a loose mesh, 14 x 10 (Fig. 160, left) Qose
weaves arc stronger and more protective.
ones are softer and more absorbent
Gauze IS used alone or along with more cficc-
live absorbents such as surgical cotton, ra)on
and cellulose It u filmaicd. for example, by
distributing a thm even la}cr of cotton be-
tween folds of gauze
ItajoR and Cellulose. Ra)on, one of (he
earliest of the s)nihclic fibers, is becoming
more widely used for surgical dressings Most
used 1 $ tliat made by the viscose process in
which either wood pulp or short fiMr cotton
(lintcrs) IS dissolved m causuc soda and
carbon disulfide and then forced throu^
spinnerets into an acid salt bath to form
filaments of cellulose In comparison with
cotton, rayon is chimed to be more absorbent
and to abvoib more quickly, have less lint,
better shelf life and present no static hazard
Cellulose derived from bleached sulphite
wood pulp and made mto thm laycn of
creped paper* is used to replace cotton as
an absorbent filler m some dressmgs
Pnmary and secondary dressings arc the
two mayor catcgoncs of surgical dressings
Primary dressings arc mtended for direct con-
tact with wounds Secondary dressmgs arc
applied over primary ones or to areas where
no wounds exist. Dressmgs with which the
community pharmacist should be familiar m
each category will be described
Prlmary Drlssincs
Gauze Dressings. Prunaiy dressings must
be stcnic and absorbent Cotton gauze is the
basic cloth for most of these dressings Gauze
IS manufactured in a vancty of meshes in
bolts, 100 yards by 36 inches Bulk supplies
arc not sterile and arc used chiefly by hos-
pitals and other consumers who have facil-
ities for stenlizauon Usual packages contain
28 X 24-mcsh or 24 x 20-mcsh gauze cut
into 1-yard or 5-yard lengths, folded to 4V6'
inch widths (8 plies or layers), urapped in
paper, rolled, placed m sealed cartons and
stcnlized These arc used cbicQy m outpatient
and emergency rooms and m doctors’ offices
Gauze Pads. Gauze pads or sponges are
made by folding 20 x 12-mcsh surgical gauze
into squares or rectangles wiUi 8 to 32 laycn
(Fig 160, rig/it) The folding pattern IS such
that all cut edges are mside and the pad may
be unfolded lengthwise without exposing cut
edges or loose threads Twelve-ply pads rang-
ing from 2x2 inches to 4 x 4 mehes, placed
in mdividual sealed glossinc envelopes and
then sterilized and packaged m cartons of 12,
25 or 1 (X), are supplied to pharmacies under a
variety of trade names t Sponges arc also
made of filmatcd gauze which is softer, has
increased absorptive power and tends to carry
drainage away from the wound Pads may be
filmatcd with cotton, rayon or either of these
plus a center layer of cellulose Bulk pack-
ages, sterile or otherwise, are supplied to
hospitals
Gauze dressings may adhere to wounds, in
effect being glued on as the absorbed exudate
does vvithio the network of gauze threads
Removal is painful and damaging. Attempts
* Ceitucotiun. Bauer & Black, Chicago III
t S(cn PaJ, Johiuoa & Johnson New Bruoswick,
N I , Economy PaJs Parke Davu Detroit, Micb
Surgical Dressings and Relafed Supplies 453
have been made to provide nonadherent
dressings by modifymg the surface which is
to be m contact with the wound Polyethylene
or other plastic films* are used, for example
Gauze, cotton or cellulose, alone or com-
bined, are used as absorbent backings The
plastic film IS pierced with multiple perfora-
tions or with slits to allow absorption and
ventilation Another form of nonadherent
padf is made from a rayon gauze impreg-
nated with a bland water-m-oil emulsion m
such a way as to leave the pores open This
^pe IS said to be less adherent and less
maceratmg than that faced with plastic*®
Gauze saturated with white petrolatum is
also available m various shapes and sizes for
use as a protective, nonadherent dressing
Specifications for petrolatum gauze are given
in the Sterile dressmgs are indi
vidually packaged m sealed alummum foil
envelopes or, m the case of selvage stops, m
a sealed plastic tube The occlusive action of
this dressmg may or may not be desirable m
given situations ClinicaJ tnab of nonadher-
ent dressmgs have led to confiicting re-
ports Prelimmary experiments, both m
vitro and on animals, show lowest ad-
hesion to nontrcated cotton and suggest that
best results are obtamed with materials which
allow wounds to dry most rapidly
Special Gauze Dressmgs Specialized pn-
mary gauze dressings which are usually sup-
plied m bulk by surgical supply bouses
mclude sponges which have radio-opaque m-
serts incorporated m the gauze to pennit
detecuon by roentgenography if they should
be left in a body cavity during surgery
Laparotomy pads, which are essentially
oversize x ray-detectable sponges, fall mto
this category Selvage edge gauze strips are
strips Vi mch to 2 mches wide with both
edges woven so as to prevent shredding
These sterile slnps, either plam or medicat^
with 5 per cent iodoform, are used as pack-
ings for wounds and cavities, mastoids, tooth
sockets and the like to stop bleedmg or to
act as dramage wicks They are packaged
m sterile glass jars Dressmg combines are
designed for absorpUon of large volumes of
• Tcifa Pads, Bauer & Black, Perfron Pads John
son & Johnson
t AdapUc Non Adhering Dressing Johnson &
Johnson
blood and exudations from wounds The
basic consists of a layer of absorbent
cotton about 1 mch thick backed up by a
layer of nonabsorbent cotton The cotton is
enclosed m a gauze cover The absorbent
side is placed next to the wound, and the
backmg serves to protect clothmg or bed-
dmg against flow through A number of sizes
arc made A modified type with a layer of
cellulose between two layers of absorbent
cotton IS intended for use when topped by
still a second pad
Adhesne Absorbent Bandage U S P^^^ is
well known under a variety of trade names,!
smee this handy form of compress is widely
used as a dressmg for small wounds Each
bandage is an mdividual sterile dressing com
posed of a small pad of folded gauze affixed
to the center of an overlappmg piece of ad
hesive plaster The adhesive surfaces and the
face of the pad are protected by coverings of
crmolme, polyethylene or similar materials
arranged so that they can be easily peeled oil
without touching the pad TTie adhesive
plaster backing of the pad is perforated to
permit ventilation of the wound Plasters may
be cloth-backed, sometimes waterproofed,
white or flesh-colored Currently, plastic-
backed tapes are more popular because they
are thinner, waterproof and less conspicuous
when applied Elastic tapes§ are also used
Some brands have nonadherent pads surfaced
with perforated plastic films Pads impreg-
nated with merbromm, lyrothncm, mtrofura
zone and other anU infective agents are sup
plied, but the need for medication applied
this way is questionable Severe competition
among manufacturers has led to a prolifera
tion of sizes, shapes and even of colors In
dividual bandages are sealed m paper en
velopes and sterilized These are packaged
ID tins or boxes which may contam all one
size and shape of bandage or an assortment
of sizes or shapes
E)e pads are oval shaped, about x
2% mches, and are made of absorbent
cotton covered by a fine mesh gauze They
are applied as dressmgs to protect mjured
t Readi Bandages Parke, Davis & Co Curad
Ptasac Bandages, Bauer & Btack Band Aid Ad
hesive Bandages, Johnson & Johnson
i Elastoplast, Duke Laboratoncs, Inc S Nor
walk. Conn.
454
Prescription Accessories and Related Items
e)cs, usually being held m place by clear
plasuc tapes The pads arc scaled m indi-
vidual glassme envelopes, then sterilized
Fifty envelopes arc packaged m a carton A
diflcrcntly shaped and larger pad with a non-
woven cotton fabric cover is also available
Secondary Dressings
Secondary dressings arc used to hold pn
niary dressings in place, give additional sup-
port and protection to the injured area,
supply compression when needed and splmt
or immobilize portions of the body Since
they arc not intended to contact wounds
directly, secondary dressings need not be
stenie
Adhesive Plasters. Adhesive plaster, com
monly known as adliesive tape, consists of a
fabric or a film evenly coated on one side
with a pressure sensitive adhesive mixture
The foundation may be a plain weave cotton
cloth, a resm-eoated cloth for water re-
peUvney, a napped flannel for moleskin, felt
tor chiropodists tape, clastic woven cloth or
films of plastics such as polyvmyl chloride *
The two principal comjranents of the ad
hesive mass arc the elastomer base and a
rcsio The latter component adds tackiness
or ' quick-stick" properties Antioxidants,
plasticizers coloring agents and fillers such
as zinc oxide are added to create a balanced
blend of adhesion, cohesion, sirctchmess and
elasticity Unvulcanizcd crepe rubber is a
common elastomer, but synthetics such os
polyisobut)]enc arc beginning to be used In
the process of manufacturing cloth backed
tapes, the adiicsive mass is heat softened, laid
on the backing and then spread over the sur-
face and mto the interstices of the cloth by
passing the plaster between rolls of a calender
stack Plastic film backmg cannot be cal-
endered but is coated by a solvent spreading
process * With the cxccpuon of some types
with specialized backings, tapes arc cut into
widths from 14 to 4 inches Lengths of 1 to
10 yards are wound into rolls on spools
Individual metal spools with protective snap-
on metal sleeves are stocked m most phar-
macies Specialized plastic dispensers with
built in cutters arc recent mnovations Rolls,
12 inches by 10 )ards, uncut or precut into
widths with uniform or assorted widths on a
smgic roll, arc packed in mctal*cappcd, stiff
cardboard cylinders for the use of hospitals
or physicians Inexpensive tapes usually have
lighter weight cloth backings but arc quite
for most purposes Tapes with an
extra heavy cloth backmg should be recom-
mended for strappmg and other bandaging
procedures requiring high tensile strength
Water repellent tapes arc needed when the
bandaged part must be protected from water
Plastic tapes are strong, thm, waterproof, un-
allectcd by soap or grease and may be
slightly elastic Gear plastic tapes arc least
visible on skm surfaces Adhesive tapes which
have clastic cloth backs are described m the
section on elastic bandages (page 427)
Moleskin is a thick, soft, napped cotton
used for cusbionmg purposes Moleskin ad-
hesive is used m orthopedic conditions where
soft tissue traction is required or where an
extremity is to be supported and cushioned
at the same tune It can be cut to provide
padding for corns, calluses, bunions and the
like Chiropodist Adhesive Felt* is used for
the same foot disorders It is, perhaps, more
resilient and phable than molcskm Both
molcsbn and felt backed adhesives are pack-
aged in wide rolls faced with cnnoliae or
other protective covcringr-
Adhesive tape has multiple uses “ It serves
to hold primary dressings m place and pro-
tect them In orthopedic work, adhesive tape,
plain and elastic, is applied to immobilize
injured lunbs and jomts Strapping the chest
with adhesive tape when the nbs arc broken
reduces discomfort and hastens healing
Coaches and trainers of athletes make hberd
use of support by adhesive tape®® to treat
and prevent injunes When cut into buiter-
fiy shapes, adhesive tape can be used m place
of skm sutures to close small wounds or to
reinforce healing wounds after sutures are
removed Individually wrapped sterile butter-
fly ^pe closures are available
In general, proper ways to apply and re-
move adhesive tapes arc not Imown to lay
people who, instead, rely on misconceptions
passed along from others The pharmacist
can ascertam readily the intended use of the
* Fell u a fabric produced by the maiUog or
feJung togeiher of fibrous oiatenals such as wool
hair or furs, Chiropodist Adhesive Fell (Parke
Davu) u 83 per cent wool 17 per cent rayon.
Surgicat Dressings and Relafed Supplies 455
tape and should offer advice with respect to
best procedures to follow Tape should be
applied only to a clean, dry surface, moisture,
oils, grease and powders mterfere with ad-
hesion. Improvement of adhesive masses has
removed the need for pnor application of
Compound Benzom Tmcture to skm as a
tackiher Tape should not be used to cover
lodme tmcture or counterimtant liniments
Adhesive tape may be removed without pam
or trauma if done slowly and with the aid of
solvents capable of dissolvmg or looseiung
the adhesive mass Carbon tetrachloride,
ether, benzme or mineral oil can be applied
with cotton to the back of the tape and
allowed to soak through In a few moments
the edge of the tape can be peeled back and
removd started It is often more satisfactory
to hold the tape tightly and to push the skin
away from it rather than to pull upon the
tape More solvent can be appbed along the
edge as necessary Rippmg of the tape oil
rapidly is no longer done To prevent pam
and stram on a wound, adhesive should be
pulled toward the wound rather than away
from it^* Tape which passes across a dress
mg should be cut at the edge of the dressmg
and the remainder removed from the skm
separately. Remnants of the adhesive should
be swabbed of! with solvents The skm should
be washed and dned after these solvents have
been used.
Reactivity to Adhesive Plasters. The esti-
mate that the mcidence of skm reactions to
adhesive plasters lies between I and S per
cent is probably too low Some mvesUga
tors have shown that nearly 50 per cent of
their test subjects developed skm changes
foUowmg application of ordinary adhesive
plasters Complamts about skm re
actions are voiced to the pharmacist who,
therefore, should be informed concemmg
them He also should be able to evaluate
claims that one tape is less likely than an-
other to produce untoward reactions
While there is not complete agreement as
to the etiology of the reactions, Russell and
Thorne^®* suggest that reacuoos of at least
5 types may develop, owing variously to the
following causes Trauma of removal, unta-
tion by the adhesiv e, maceration of the homy
la)er followmg retention of sweat and serous
discharges, disturbance of balance of skm
bacterial flora, eczematous sensitization Re-
union due to removal develops a mmute or
two after removal of plaster, especially at
hairy sites It generally disappears quickly
also The reaction is greatest with more
tacky plasters It can be prevented almost
completely by usmg a solvent or a detackifier
such as ether or mmeral oil to assist m re-
movmg the tape
Irritation by the adhesive arises from me-
chanical or chemical stimulation of keratm
formation, mterference with desquamation,
pluggmg of pilosebaceous folhcles and, prob-
ably, from other unknown causes also It is
more pronounced with people who perspue
heavily and m hot, humid surroundmgs It
appears clmically 5 days or more after ap-
plication The more adhesive the plaster, the
greater the imtaiion Waterproof and ordi-
nary plasters with similar adhesiveness pro-
duce equivalent irritation, suggestmg that the
operative factor lies with the physicochemi-
cal properties of the plaster, not with the
degree of permeability of the backing
Xvhile sweat retention and maceration of
the homy layer may lead to mfection or m-
fectious eczema, plasters with porous back-
mgs are not always found to be less imtatmg
than nonporous ones However, lack of
imtation by a newly developed surgical tape
which IS discussed later is attributed in part
to porosity of the backing and consequent ab
sence of skm maceration Disturbance of the
balance of bacterial flora on ±e skm assumes
importance only when antibacterial agents
are incoq>oratcd m the adhesive mass, m
which case there is some possibility of an
“ecologic” drug eruption
Ibe mcidence of eczematous sensitization
1 $ much smaller than that of reactions due
to direct contact imlation How-
ever, Kiel*® has pomted out that allergic con-
tact owmg to adhesive tape is by no means
rare m the absolute sense It develops after
a latent period of days on the first exposure
or after a few hours on subsequent ones
Many of the constituents of the usually com-
plex adhesive mass have been implicated,
among them colophony rcsm (rosm) , chlorox-
ylenol (an anUseptic sometimes used) and
the protems m rubber Sensitivity to teipcne
structures m resins and rubber has been sug-
gested as mitiatmg the reaction.®*®
Surgical Dresstngs and Related Supplies 455
tape and should offer advice with respect to
best procedures to follow Tape should be
applied only to a clean, dry surface, moisture,
oils, grease and powders interfere with ad-
hesion Improvement of adhesive masses has
removed the need for prior application of
Compound Benzom Tincture to skm as a
tackifier Tape should not be used to cover
iodine tmcture or counterimtant liniments
Adhesive tape may be removed without pain
or trauma if done slowly and with the aid of
solvents capable of dissolvmg or loosening
the adhesive mass Carbon tetrachloride,
ether, benzme or mineral oil can be applied
with cotton to the back of the tape and
allowed to soak through In a few moments
the edge of the tape can be peeled back and
remov^ started It is often more satisfactory
to hold the tape tightly and to push the skm
away from it rather than to pull upon the
tape More solvent can be applied along the
edge as necessary Ripping of the tape off
rapidly is no longer done To prevent pain
and strain on a wound, adhesive should be
pulled toward the wound rather than away
from It “f* Tape which passes across a dress-
mg should be cut at the edge of the dressmg
and the remamder removed from the skm
separately Remnants of the adhesive should
be swabbed off with solvents The skin should
be washed and dried after these solvents have
been used.
Reactivity to Adhesive Plasters. The esti-
mate that the incidence of skm reactions to
adhesive plasters lies between 1 and 5 per
cent IS probably too low Some mvestiga
tors have shown that nearly 50 per cent of
their test subjects developed skin changes
following application of ordmary adhesive
plasters Complamts about sUn re-
actions are voiced to the pharmacist who,
therefore, should be informed concerning
them He also should be able to evaluate
claims that one tape is less Lkely than an-
other to produce untoward reactions
\Vhne there is not complete agreement as
to the etiology of the reactions, Russell and
Thorne*®^ suggest that reactions of at least
5 tjpes may develop, owmg variously to the
followmg causes Trauma of removal, irrita-
tion by ^e adhesive, maceration of the homy
la)er following retention of sweat and serous
discharges, disturbance of balance of skin
bacterial flora, eczematous sensitization Re-
action due to removal develops a mmute or
two after removal of plaster, especially at
hairy sites It generally disappears quickly
also The reaction is greatest with more
tad^ plasters It can be prevented almost
completely by usmg a solvent or a detackifier
such as ether or mmeral oil to assist m re-
movmg the tape
Imtaiion by the adhesive arises from me-
chanical or chemical stimulation of keratm
formation, mterference with desquamation,
pluggmg of pilosebaceous folhcles and, prob-
ably, from other unknown causes also It is
more pronounced with people who perspire
heavily and m hot, humid surroundings It
appears clmically 5 days or more after ap-
plication The more adhesive the plaster, the
greater the imiation Waterproof and ordi-
nary plasters with similar adhesiveness pro-
duce equivalent imtation, suggestmg that the
operative factor hes with the physicochemi-
cal properties of the plaster, not with the
degree of permeability of the backmg ***
While sweat retention and maceration of
the homy layer may lead to infection or m-
fecuous eczema, plasters with porous back-
mgs are not always found to be less imtatmg
than nonporous ones However, lack of
irritation by a newly developed surgical tape
which IS discussed later is attributed m part
to porosity of the backing and consequent ab
sence of skm maceration Disturbance of the
balance of bacterial flora on the skm assumes
importance only when antibacterial agents
are incorporated m the adhesive mass, m
which case there is some possibility of an
“ecologic drug eruption
The madence of eczematous sensitization
IS much smaller than that of reactions due
to direct contact irritation How-
ever, Kiel®* has pomted out that allergic con-
tact owmg to adhesive tape is by no means
rare m the absolute sense It develops after
a latent penod of days on the first exposure
or after a few hours on subsequent ones
Many of the constituents of the usually com-
plex adhesive mass have been implicated,
among them colophony resm (rosm) , chlorox-
ylcnol (an antiseptic sometimes used) and
the proteins in rubber Sensitivity to terpene
structures m resins and rubber has been
gested as mitiatingthe reaction.*”
Fia 161 Applyiog tubular gauze to a
finger (Top) A length of gauze slightly
longer than twice the length of the finger
IS threaded over the applicator and placed
on the finger Breaks in the skin should
first be covered with a sterile dressing
(Center) The applicator is pulled od the
finger and twisted one full turn (Dotiom)
The opplicator is pushed forward again to
apply a second layer of gauze and seal the
tip end The base of the bandage should
be fastened down with adhesive (ape
Ityporeactivc Tapes. la attempts to eltm*
mate skm tmtations caused by adhesive
tapes, a number of hyporeactive tapes (also
called hypoallergenic) have been fonnulated
using specially purified ingredients and a
minimally compleit mass A formula for a
mass made with synthetic substitutes for both
rubber and resins has been advanced as
hypoa'i^CTgenic ll is nol as adhesive as
more usual formulations and is useful pn-
manly for patch testing Tapes* with single-
ingredient masses haie been marketed, gen-
erally, these tapes arc less adhesive also
Peck and co-workers*” believe the most
common type of irntation to be due to eleva-
tion m pH and changes in bacterial flora under
* Dermicel Surgical Tape Johnson & Johnson
the depression of bacterial flora by these fatty
aad salts Humphries” reported marked re-
duction in adhesive tape dermatitis with tape
of the same brandf and also found better
adhesion, less pruriUs and less skm macera-
tion Others** found no difTercnce between
the pnoiaiy irritant qualities of this tape and
two others with standard adhesive masses
It IS probable that a certain amount of non-
specific irritation by adhesive plaster cannot
be avoided **
An mtcrestmg new tapej now seems to
offer advantages of less occlusion and irrita-
tion** ** without sacrifice of adhesiveness
The backing material is rayon in a thin,
porous, nonwoven web construction The
adhesive is a synthetic copolymer — perhaps
of acrylate esters'* *** — ^which is coated on
the backing without blocking the micropores
of the web Therefore, ventilation is mini-
mally impeded When smoothed down firmly
on dean dry skm, the tape adheres tightly,
yet It can be peeled off easily without trauma
Hairs are not entrapped in the adhesive It
does not leave a sticky residue on the skin
The tape is not dislodged by secretions,
perspiration or soaking Complete lack of
skm imtatjon or maceration is clauned**
Rolls of tape to 3 inches by 10 yards
are available m cartons of 24 to 6 rolls Since
the tape unwinds readily and tears easily,
special dispensers are not necessary The
fragile appearance of the tape may delay its
general acceptance by the public Claims for
It have yet to meet the test of widespread use
Liquid Adhesive. An alert pharmacist will
find opportunities to inform his patrons of less
familiar adhesive materials that they may use
to their advantage For mstance, a liquid ad
besive massi is sometimes more convenient
than the conventional tapes for adhenng
small dressings over minor wounds or skin
eruptions m areas that are difficult to band-
age It may be applied directly from the tube
t Pro-Cap, Seamless Rubber Co . New Jtaven
Coon.
1 3 M brand Micropore Surgical Tape, Minnesota
Mining and Manufacturing Co , St Paul, Minn
I Duo Surgical Adhesive Johnson & Johnson
Surgical Dressings and Related Supplies 457
so as to fonn an elastic ring around the area
to be protected For example, boils on the
back of the neck can be covered with a
small piece of sterile gauze, a rmg of liquid
adhesive placed around the gauze and a
slightly larger piece of soft flannel placed
over all so that its outer edges be
afBxed to the skm Cellulose film products
such as Scotch* tape are well known for
household uses They may also be used to
hold face dressmgs and eye pads in place
when a product less conspicuous than ordi-
nary tape is desirable
Roller Bandage. Gauze bandage, also
known as bandage rolls and roller bandage,
may be made to comply with US P stand-
ards for Absorbent Gauze^®^, m which case
Type I gauze {44 x 36 mesh) is used Most
bandage rolls stocked by pharmacists for use
by the general public W1 into this category
They are available m widths of 1 to 4 inches
X 10 yards Edges are treated to minunize
ravelmg Individual rolls are paper-wrapped,
sealed in boxes and sterilized after packag
tag Bandage rolls of looser meshes as well
as of unbleached muslin (56 x 60 mesh) are
also made for mstitutions and physicians
primarily These rolls are nonsterfle They
may be cut into standard widths and pack
aged by paper-banding a number of rolls
together Uncut rolls, 36 inches wide or more,
are also supplied
Gauze bandages are used to hold on dress
mgs and, occasionally, to supply slight pres-
sure or support They ate not mtended for
duect application to wounds Musim roUer
bandages are stronger than gauze and are
used to hold splmts or bull^ dressmgs m
place Wrappmg with roller bandage is an
art requiring much practice if neat results
are to be obtamed First aid manuals and
other sources'** illustrate desirable technics
The pharmacist called on to render first aid
will be well advised to use one of the more
easily applied bandages descnbed below
Triangular Bandages. The Esmarch tn-
angular bandage has numerous uses in first
aid'" because it is quickly and easily applied
by one reasonably acquainted with its capa-
bilities Head dressings, bmders for splmts
for broken bones and arm slmgs are readily
* Minnesota Ntimng and Manufactunng Co
Fig 162 Conforming bandage The
edges have been turned back so that the
2 ply construction and the mdividua!
threads can be seen
made from these bandages They are isosceles
right tnangles of bleached muslin approxi-
mately 54 inches m length at the base Non-
stenle packages of various sorts are avail-
able
Tubular Bandage. The pharmacist may
enhance his stature as an advisor about first-
aid supplies by tellmg his chents about unique
Items and showing how they may be used
with advantage over highly promoted con-
ventional products obtamable from self-
service racks m nonprofessional outlets For
example, a seamless tubular gauze bandagef
can supersede the traditional roller bandage
for many uses It is apphed much more
qaicWy and, generally, it makes a neater,
more comfortable covering with less bulk,
especially over areas diflScult to wrap There
are 6 sizes which are supplied in 10-yard and
50 yarf rolls and 4 sizes m 5-yard rolls Sizes
1 and 2, which are used for small and large
fingers and toes, are packaged with an apph-
t Surgitube, Surgitubc Products Corporation
Brt>nx.N Y
458 Prescription Accessories and Retoted Items
cator and instructions for use (Fig 161)
Intermediate sizes fit oNcr hands, feet and
elbows The laigest tubing fits over the head
Both white and flesh-colored rolls are made
The bandage as supplied is not sterilized
Conforming Bandage The discovery that
preshrunk cotton gauze fibers become kiniqr
and stick to each other’ led to the develop
ment of a new form of roller bandage • A
14 X 10 mesh gauze is used and the edges are
folded to the center (Fig 1 62 ) Owing to the
loose mesh and the enmped threads, the
bandage is soft and conforms readily to body
contouR, and overlapped laycR gnp one an-
other, thus lessening slip Because of its
two-way stretch it »s less likely to constrict
STiVcllmg areas The 2 ply construction gives
the bandage greater absorbency The con-
forming bandage should be recommended for
household use, since even a novice can make
a neat covering with it Individual stcnle rolls
are marketed m sizes from 1 to 4 inches x 5
yards Bags containing nonstenle rolls up to
6 inch widths are also available This gauze
with a filler of rayon is used m institutions as
a highly absorbent elastic compression dress
ingt for breasts, amputee stumps of limbs
and bums
Self*adhcnng Bandage. Self adhering
gauze^ IS a useful form of bandage about
which the lay public is not well informed
This is bleached absorbent gauze (32 x 28
mesh) impregnated with natural rubber latex
so that the gauze slicks only to itself, not to
skin or hair The bandage is dry to the touch
It can replace adhesive tape as a mfld sup
port for strains or can function as a bandage
for hofding on dressings Its advantage is
that overlapping lajcR can be pressed to-
gether and made to cohere The bandage is
nonocclusive, since the gauze meshes are not
filled in Water does not materially affect the
cohcsivcness An od resistant form impreg-
nated With synthetic resins is available In-
dividually boxed sterile rolls of to 2 inches
by I'A, yards arc supplied for pharmacies,
and rolls 12 inches by 10 yards are cut to
order for msliiuiions
• Red Cross Impro^cd Bandage Klmg Confoim
Bandage, lohnson & Johnson.
t Compression Roll Johnson & Johnson
t Gatateic Bandage General Bandages Joe
Morton Grove, III
Plaster ol Paris bandages are used in or-
thopedic work to make plaster casts for
fractures and for other conditions m which
immobilization and support are necessary
Plaster of Pans (CaSOi'ViHjO) is a white
amorphous powder made by partial dehydra-
tion of gypsum (CaS04*2H20) The plaster
reacts exothermically with water to form
crystals of gypsum which interlock to form a
hard, ngid mass on drying The plaster can
be molded to fit the nintours of the area
to which It is being applied, but after a certam
cntical point — known as the setting time — at
which ciystallization occurs m the harden-
ing process, further movement of the plaster
causes it to crumble ** Bandages are made by
rolling and rubbing the plaster into meshes of
crinoline § Advantages are claimed for those
made by hand,” but machine made propn-
clary bandages are used much more fre-
quently
The two mam kinds of plaster bandages
differ in the manner m which the plaster is
resent m the bandage The loose plaster
andages are made by sprinkling the dry
powder m a smooth, even layer on the
cnnolme and rolling the cnnolme over on it-
self so as to hold m the powder The hard-
coated plaster bandages are made by apply-
ing a |mste or an emulsion of the plaster to
the crinoline and then baking it The second
type is preferred by most orthopedic men be-
cause It 1$ less messy to handle, wets more
rapidly and loses less plaster in the wetting
process The hard-coated form|| is supplied
ID roUs of 2 to 8 inches x 3 or 5 yards (Fig
163) It IS also supplied as straight board
fifce spfintsff made 6y cutting 3-jnch, 4-mcfi
and 5-inch widths of hard-coated bandage
into 15-mch, 30 inch or 45-mch lengths
Splints are used to reuiforcc casts and speed
up cast raabng Plaster of Pans bandages arc
sometimes packaged individually m sealed
polyethylene bags# or m waterproof poly-
ethylene papcR* • to protect agamst moisture
The time required for the plaster to set
after It IS wetted depends on a number of
I Cnnolme is a loosely woven bleached gauze
MilTened by starch
I) Specialist Plaster of Pans Bandages Specialist
Filler of Pans Splints, Johnson & Jotuison
# Readi-Cast Parke Davis & Co
Ostic, Bauer & Black
Surgica! Dressings and Related Supplies 459
Fio 163 Bandages used m casts Left to right stockinette cotton felt hard coated plaster
of Pans bandage
factors Th^e are controlled to a degree in
the manufacture of the bandages and the
splmts, most of which fall into one of two
ranges of setting time The extra fast setting
which crystallizes m 2 to 4 nunutes, is useful
for foot plasters on very small children The
fast setting, which crystallizes m 5 to 8 min
utes, IS used for most cast work Setting
can be hastened by adding either sodium
chloride or alum or delayed by adding borax,
but the plaster is made bnttle Experienced
workers modify settmg times while they are
makmg the cast by controlling the tempera-
ture of the water used warrn water acceler-
ates settmg, cool water delays it
Formalm resms have been found to add
waterproofing and strength to plaster of
Pans casts, temg especially useful for walk-
mg casts, for example Casts may be made
one half the thickness and the weight of an
ordmaiy cast and about 4 times as strong **
The resm may be used as a powder to which
water and a catalyst, usually ammonium
chlonde, are added The regular fast-settmg
plaster bandages are wetted with this solu
tion and applied as usual Polymerization of
the resm m situ forms a hard waterproof,
easily cleaned cast Bandages* contammg
resm, plaster and catalyst as one unit ready
for wettmg are marketed also Casts can be
made entirely of synthetic resms, but this is
not commonly done m this country
Smce plaster of Pans bandages are used
by specialists tramed m makmg casts, phar-
macists are not often asked about technics
of application
^mpment such as stainless steel buckets,
plaster knives, spreaders, benders and cast
cutters are genei^ly obtamed from surgical
supply houses However, pharmacies may
stock matenals such as stockmette and sur-
gical (sheet) waddmg, both of which are
used as paddmgs under casts Stockmette,
which is slipped on directly over the skm, is
a seamless tubular material knit of un
bleached nonabsorbent cotton yam (Fig
* ZOROC Resm Plaster Baudaies Johnson &
Johnson
460
Prejcnption Accessories ond Related Items
163) The knitted weave confers elasticity
to allow the stockinette to adapt itself to body
conformations The 25 yard rolls come m
widths ranging from 2 to 12 inches It is not
recommended for use over acute fractures or
immediately postopcralively because « acts
as a constricting banda^ and may impair
circulation Sheet wadding is used for al-
most all casts — usually bemg wound over
stockmettc It is made from bleached non-
absorbent cotton which has been glazed on
both sides to give it tensile streng^ and to
avoid matting or lumping It is supplied to
6-yard lengths as uncut sheets 36 inches wide
as well as rolls 3 to 8 inches wide A non-
woven cotton felt fabric,* avaflable m rolk
2 to 6 inches % 4 ^ards, has properties of
softness, elasticity, conformability and
strength which make it suitable for ortho-
pedic cast padding
Packagisc and Storage of
Surgical Dressings
Surgical dressings arc labeled to identify
(hem either as stenie or as noasterdizcd.
Each stenle item is sealed in an individual
package labeled to the effect that stcniity will
not be guaranteed if the package bears evi-
dence of damage or has been opened previ-
ously Since openmg the packages usually
destroys the resale value, pharmacists tend to
dispense surgical dressings without examin-
ing Iheir construction or establisbmg their
quality For the sake of obtaining this neces-
sary information, small packages should be
opened or samples should be obtained Sur
gical dressings should be stored in closed
cabmets that protect them from dust m order
to be consistent with the concept of stcniity
When placed on open shelves, frequent dust-
ing is mandatory These items should not be
stored near sources of heat since absorbent,
color or adhesiveness may be affected ad-
versely by elevated temperatures
Related Supplies
A number of items are related to surgical
dressings m the sense that there is a sunilar-
it) m construction and an association tn use
Into this category fall obstetneal pads or
sanitary napkins, vaginal tampons, medi-
cated plasters, cellulose tissues, spray-on
wound dressings, underpads, disposable
* Webnl Bandages. Bauer & Black
diapers and surgical masks, for example The
last three on this list are described in the
following sections
Disposable Underpads. By preventing
soilage of bed linens, disposable underpads
may save both time and energy for those en-
gaged in home and institutional nursing.*-^
These pads are generally composed of a
highly absorbent filler sandwiched between
a soft fabne facing and a water-repellent
backing Several brands and qualities are
available The more efficient stylcsf have a
nonwoven fabric facing, a cellulose filler and
a polyethylene backing Less expensive onesj
may have a paper facing, cellulose filler and
a repellent backing paper The usual size is
MVi X 24 inches with a large pad, 23 x 24
inches also is supplied in some brands
Usually, 200 pads are packed m a case for
institutional use Smaller quantities per
package arc supplied for home use |
Disposable diapers are basically similar to
disposable underpads m design They may be
complete diapers, the whole being discarded
when soiled or wet, or they may be single-
use absorbent pads which are inserted as
needed into a reusable plastic or nylon holder
Several brands are marketed, each m a range
of sizes They are most used as a convenience
for traveling Their use may also lessen the
danger of contagious diseases such as im-
peugo
Surgical Masks Face masks of various
types arc used m operating rooms and else-
where to mmunizc transmission of air borne
orgamsms They arc intended to filter both
inspired and expired air so as to stop passage
of pathogens in either direction They are
shaped to fit over the mouth and the nose
and to extend under the chin to keep perspira-
tion from dropping into the work area Tapes
are attached so that the masks may be tied
on The simplest type is made from a single
layer of finely w oven fabric Another is made
of 4-pIy fine mesh surgical gauze A third
type has a Danncl filter covered on both sides
with fine mesh gauze Each of these masks
has a flexible metal strip (sometimes remov-
t Lornv Undeqiath Johiuon & Johnsoo, locoa
tineot Pads Bauer & Black
t Bed Pads Johnson & Johnson Disposable
Underpads Parke. Davis & Co
(Chux Disposable Underpads Chicopee Mills
Inc. New York N Y
)
Crutches and Canes 461
Fio 164 (Le//) Forms
of crutches Left to
right standard wooden
double upright adjust
able wooden double up
right Canadian wooden
adjustable Lofstrand alu
minum and adjustable
double upright alumi
num with wooden axil
lary rest and hand grip
(Right) The tripod po-
sition
able) in the upper seam to allow the mask
to be molded over the nose A close fit is
necessary to prevent the breath from blowing
op over the upper margm However, wearers
ohen complam that eyeglasses are fogged by
condensation of moisture from the breath
Inlerfcience with breathing, muffling of the
voice and wetness of the mesh after short
periods m use are other discomforts which
are endured to some degree A new surgical
mask* mcorporatmg a finely porous filter
fabnc m a lightwei^t plastic shell seems to
offer advantages m both efficiency and com-
fort The contour shape keeps the mask from
touching the mouth and the nostrils, while an
adjustable nosepiece prevents escape of air
around the edges The mask is held on by an
elastic band It is claimed that current modeb
are 98 per cent effective m bacterial control*®^
over long penods of time An earlier design
was found to be 86 to 90 per cent efficient
m bacterial filtration over a test penod of
30 minutes, whereas a gauze mask was 30 to
40 per cent efficient in a 2 minute test and
only 8 to 10 per cent efficient at the end of
30 minutes The mask is designed for one
*Aseptex surgical mask Minnesota Mining &
Manufactunng Co
tune use only so as to elimmate costs of
washing and re sterilizabon Only boxes con-
tammg 50 masks are available Although the
desirabili^ of packaging these masks suitably
for hune use to prevent spread of upper re
spiratoiy infections from mother to child is
recognized, apparently it will be some time
before this will be done *** In the meantime,
only relatively mefficient gauze masks are
available for this purpose
CRUTCHES AND CANES
Cnifches Pharmacists often sell or rent
cratches to persons who are temporarily dis
abled due to a broken leg a sprained ankle
or other crippling injury This service entaib
fittmg appropriate cratches to the mdividual
and iDstractmg m their use Both alummum
and hardwood cratches are available Alu-
minum ones are lighter and stronger but
more expensive Standard or plain crutches
are fixed m length, adjustable ones can be
set to several lengths Several typical cratches
are shown in Figure 164 (/e/0
Cratches with double uprights and a hand
gnp are best for short term use by novi<»s,
as considerable skill and strength are needed
462 Prescnption Accessonet and Retofed Items
Table 91 Standard Crutch OtART
Height of Person
(inches)
Crutch Size*
52
53
36
54
55
38
56
57
40
58
59
42
60
61
44
62
63
46
64
65
48
66
67
50
68
69
52
70
71
54
72
73
56
74
75
58
76
77
60
* If height in inches is an odd number subtract
17 to get crutch length if even subtract 1$
to handle most of the other styles The phar-
macist may prefer to stock adjustable
crutches in this style, since there are only
four sizes to be carried The center post is
pierced by a number of holes spaced 2 inches
apart along its length Two of these boles arc
lined up tt iih holes through the uprights, long
bolts are passed through, and wing nuts are
securely attached to fasten the center post m
position and to make the crutch the desired
over all length Hand grips may be set to
4 or 5 positions by a similar bolt and nut
arrangement Crutch sizes are adjustable as
follows adult, from 48 to 60 inches, youth,
from 36 to 48 inches, child, from 30 to 36
inches and infant, from 24 to 30 mehes
Brands vary slightly in range of adjustment
Economy models of aluminum crutches are
generally supplied in two sizes only, one
adjusting from 29 to 41 inches, the other
from 42 to 60 inches
To estimate the correct size for an indi-
vidual, measure from 2 inches below the
axilla to a point about 4 inches to the side of
one foot while he is standing erect, shoulders
and pelvis m line If the patient is still bed-
nddeo, measure to the heel and add 4 inches
A standard crutch chart (Table 91) may be
posted in the crutch department The de-
sired length is obtained by moving the center
post as necessary, and the hand grip is placed
at about one third the total length To deter-
mme if the size is cxirrect, have the patient
assume the 'tnpod' position (Fig 164,
righty which will be used in walking With
the hands placed on the hand grips and the
crutch tips about 4 inches in front of and to
the side of the feet, the axillary rests should
be about 2 inches below die axillae as the
weight IS borne on the wnsts and palms The
wnsts should be bent and the elbows flexed
so that the foreann makes an angle of 15 to
20 degrees with the upper arm The crutches
should be complete with foam rubber pads
on the axillary rests and the hand grips and
with rubber crutch tips Readjust as neces-
sary Sizing may be speeded up by making
preliminary adjustment with a crutch with
a slotted center post and uprights with which
the patient’s crutches may be matched An
aluminum telescopic underarm crutch which
has an easily adjusted tubular single shaft
IS also handy for measunng patients for
crutches
Standard wooden crutches come in lengths
from 26 to 60 inches in increments of 2
inches About a dozen sizes are needed to
take care of most youths and adults (Table
91) Aluminum crutches are supplied only
m adjustable models
Amputees, poliomyelitis victims and others
who require continued use of crutches gen-
erally are fitted for crutches and taught to
use them by the medical persons treating
them Lightweight crutches of spcaal design
often arc supplied to these people at the hos-
pital or obtained from sources other than
pharmacies One of the more widely used Is
the Lofstrand aluminum crutch* (Fig 164)
•TtielAfitnind Company. Rockville Md
Crutches and Cones 463
Table 92 Handling Crutches on Stairs*
1 Hold railing with one hand t
2 Place both crutches under opposite aniLt
A Patient with one good leg, other can
bear partiS weight
To ascend To descend
3 Step up with good 3 Lower crutches and
leg bad leg to the step
below
4 Lift bad leg and 4 Bring good leg
crutches to this down to this level
level
B Patient with one good leg, other
cannot bear weight
To ascend To descend
3 Push on crutches 3 Lower crutches to
and railing to lift the step below
body so that good
leg can be placed
on the step above
4 Lift bad leg and 4 Bend good knee,
crutches to this shifting weight to
level crutches and rail
mg
5 Step down with
good foot
•Modified from Arje, F B How to teadi
crutch walking RN2^ 38, 1961 (March)
t The first 2 steps apply to all 4 procedures
The forearm ts gnpped lightly by the pivoting
cradle at the top of the crutch so that the
handle can be released without dropping the
crutch or losmg its support The crutch size
IS determined by measuring from the palm
of the hand to the floor with the arm parallel
to the body Nonadjustable crutches rangmg
from 30 to 42 mches from hand gnp to Up
are made Adjustable crutches of severd
styles and size ranges also are available Com-
ponent parts may be ordered separately
Too often, pharmaasts supply crutdics
Without being certam that the recipient knows
how to use them Instructions m how to walk
with crutches should be an integral part of
the service^® There are seven gaits for
crutch walking,^® three of which are easDy
learned (Fig 165) Negotiating stairs pre-
sents problems (Table 92) The pharmacist
should practice these procedures and be pre-
pared to demonstrate them
Crutch Accessories. Crutch arm pads,
hand-gnp cushions and crutch tips are neccs-
Fio 165 Crutch gaits A Four point
gait easiest and safest, useful when pa-
tient can bear some weight on both legs
The patient puts one crutch forward, then
tfae opposite foot, the other crutch, the
opposite fool, three weight beanng points
at aU Umes B Two-point gait weight on
one leg and opposite crutch bring other
leg and crutch forward together and shift
weight to them, faster than the four point
C Three point gait used when one leg is
unable to bear weight (symbolized by toe
only), but tfae other is strong enough to
bear all of the patient’s weight, weak leg
and both crutches are advanced together
and the weight is balanced on them as the
good leg is moved forward
sary accessories Arm pads are usually made
of sponge rubber, sometimes reinforced by
fabnc Immgs Only one size is made, as this
can be stretched over the arm-piece of all
standard adult-size crutches The pad is used
to protect the axilla against faction and m-
jtny, but Its presence creates the erroneous
464
Preicriplion Accessories and Related Ilem^
Fio 166 Canes An adjustable aluminum
c and a four Kcgcd cane are shown
impression that the crutch user is supposed
to support his wcigl j on the arm rests Weight
must be carried on • ic wrists and the elbows
Leaning on the a lUary rests may cause
paralj’sis of the rad' :al nerve or of the entire
brachial plexus, we yncss in the forearm, the
wrist or the hand s^iGcs the onset of this
“crutch paraljsis ” iubber hand gnp cush-
ions may be split lengthwise to permit slip-
ping oser the crute’-’hand gnp or they may
be a closed style bps are made of
rubber high m minerai^cr content to make
them abrasion resistant, t^^ may be fabrtc-
Uned to minimize chance of t^plches wearing
through Tips l^ve a characterwh 5 ,bapc with
a concave suction-cup design on the tettom
They cushion against jamng and prevent
sliding Crutch tips with worn-over rounded
ed^ unsafe and should be replaced
Several sizes, with internal diameters rang-
ing front % to 114 inches are made The
cnitch lip should fit tightly A little talcum
powder sprinkled on the inside of the tip
mAkes It easier to slide on Lubneatmg with
oil or grease will damage the rubber Crutches
should not be dispensed unless dressed with
arfn pads and crutch tips but the use of
hand grip cushions is not common
Canes are used by people who require less
support than that afforded by crutches
Wooden canes vary greatly in quality of
wood used and degree of omateness Alu
minum canes some in adjustable styles, are
abo avai'iable Tittmg ol canes is largely a
jnAtter of finding a length which seems to be
comfortable llie elbow should be only
slightly bent when the weight is borne on
the cane The standard cane length is 36
inches with lengths up to 44 inches available
in some brands Some aluminum canes (Fig
166 ) may be adjusted as much as 16 inches
from 22 inches to 38 inches Rubber cane
tips which serve the same functions as crutch
tips, should be attached to walking canes
The blmd man’s cane is 42 inches long, white
at the top, red at the bottom and metal-
upped Three legged and four legged canes
(Fig 166) have uses intermediate to those
of crutches and walking canes When a cane
IS used for weight bearmg it is carried beside
the disabled leg ^Vhen used for balance, it is
earned beside tJie sound leg ^
INFRARED AND ULTRAVIOLET
GENERATORS
The application of heat to parts of the
body m order to relieve muscular pain— or
for many other purposes — is one of the com
monest and the simplest forms of therapy
Radiation — the process m which an object
loses heat by emitting energy m the form of
electromagnetic waves — is an important
method of transmitting therapeutic heat.
Pharmacists supply a large number of the
h^t radiating devices used in this country
arid should be prepared to offer sound advice
concerning their selection and use
Heating Action of Infrared Rays. Hie
wavelengths used for beat therapy are in the
Infrared and Ultraviolet Generators
465
Table 93 Characteristics and Sources of Selected Spectral Regions*
Spectral Region
AND Wavelength (A)
PENETRATlONt
Physiolocic
Action
Source
Far IR
150 000 to 15000
Superficial
0 05 to 1 mm
Thermal
Dull red heaters
Carbon arc
Near IR
15 000 to 7.600
Deep
1 to 10 mm
Thermal
Luminous heaters
Sun
Carbon arc
Visible
7,600 to 3 900
Deep
10 to 1 mm
Thermal
Luminous heaters
Sun
NearUV
3,900 to 2 900
Superficial
1 toO 1 mm
Photochemical
Sun
Carbon arc
FarUV
2,900 to 1 800
Superficial
0 1 to 0 01 mm
Photochemical
Cold quartz
Mercuiy arc
* Modified from Coblentz W W Sources of ultraviolet and infra red radiation used in therapy,
JAMA 132 i78 1946
t Penetration to depth at which biologic aciion if any, may still be expected
infrared and the visible portions of the spec-
trum (Table 93) Low-temperature sources
such as hot water bottles,* electnc heating
pads* and dull red heaters emit principally
far infrared rays, while high temperature
sources such as sun and incaadesceat
lamps radiate near infrared and visible rays
When radiant energy strikes the body sur-
face, some IS reflected and the rest is ab-
sorbed m the skin and the underlymg tissues
The extent of both the reflection and the
penetration into the human body vary with
the wavelength of the mcident radiation
It IS generally agreed that significant pene-
tration (Table 93) can be expected only for
visible and near infrared radiation maximum
penctrstion occurrwg at wavelengths about
11,000 A In this range of radiation, about
40 per cent reflection occurs Far infrared
IS absorbed in the stratum comeum, near
infrared shows strongly increasmg absorp-
tion m upper layers, decreasing m lower
layers, visible light is absorbed chiefly in the
conum Both visible and infrared radiation
may reach subcutaneous tissues
In radiant heatmg, electromagnetic waves
are wmverled mto heat energy by a two-
stage mechanism In the first stage, the
absorbed radiation excites electrons m tissue
molecules to higher energy levels, vibrational
• The lotensity of radiation from hot wafer
bottles and electnc heating pads » too low to be
therapeutically significant these devices beat by
conduction, not by radiation
and rotational movements withm the mole-
cules are also mcreased In the second stage,
the excited molecules distribute the extra
eoer^ to others as they coUide during the
thermal agitation which is always present
Consequently, the absorbed energy appears
as fanetic energy of the molecules, viz , as
heat The actual distnbution of the heat
withm the tissues depends on the site of ab-
sorption, the rate of conduction to other
layers and the rate of removal of heat by
the circulatmg blood Owmg to its super-
ficial absorption, nonpenetratmg far m&ared
creates a greater sensation of warmth than
do the near infrared and the visible radia-
tions at equal mtensiues Smee the factor
Jimilin^ the intensity of radiation which may
be administered to &e patient is his own sub-
jective feeling of warmth, a greater intensity
of near infrared or visible radiation m the
penetrating range can be given before the
subject feels discomfort, and, consequently,
a greater nse in temperature of deeper tis-
sues can be achieved.*®*
Infrared generators used therapeutically
are composed of metallic conductors mounted
in the tOTler of concave reflectors and heated
by the passage of an electnc cunent There
are tw> types the infrared radiators which
operate at relatively low temperatures and
arc essentially nonlummous and the heat
lamps which operate at high temperatures
and are luminous
Hic heating element of an infrared radia-
A66
Prescription Accessories and Related Items
tor ma) be a resistance wire wound on or em-
bedded m a noncondacfing matenal A com-
mon form IS a ceramic cylinder about 2 inches
in diameter and 6 inches long with a nickel-
chromium resistance wire embedded m it In
a second style, the infrared rays are radiated
from flat circular plates made of metal which
arc heated by current floiving through resist-
ance w-ircs embedded m them The two forms
arc used similarly A third design consisting
of a nickel-chromium resistance wire inside
a fused silica tube has recently been inf/o-
duced The reflectors are placed on stands,
sometimes of the gooseneck design The m
frared radiators are marketed m smaD units
that drawr 50 to 300 watts and large ones
that draw up to 1,500 watts They operate at
a red glow (about 800° C ), emitting mostly
far infrared radiation
One form of the modem heat lamp con-
sists of a tungsten filament enclosed in a
rounded, gas ^ed, clear glass bulb which
can be screwed into a light socket The pres-
ence of the gas (argon) prevents oxidation
of the filament and allows it to be heated to
a higher temperature The lamps operate at
about 3,000° C . emitting radiation of 4,000
to 40,000 A svith maximum emission at about
11,000 to 12,000 A Shorter and longer
waves are absorbed by the glass of the bulb
The lamps come m wattages ranging from
150 to 1,500 The penetrauon effect is the
same regardless of lamp size, small (amps
are used to treat small areas such as the
hands or the feet, and large lamps are more
effective for warming larger areas of the body
such as the back Some lamps have a variable
resistance mounted in senes with the bulb
so that the power output can be regulated
Lamps are mounted at the center of alu-
minum reflectors and attached to stands of
vanous types Some are fitted with a wire
gauze protector to protect the patient from
hot fragments of glass if the bulb should
burst Several small lamps may be mounted
m a semicircular shield forming a "baker”
which can be used to heat large areas such
as the trunk
The heal lamp commonly stocked m phar-
macies differs from the one described above
mainly in that the reflector is an mtegral part
of the bulb itself The reflector is made by
depositing a thin film of alutmnum on the
mside of the funnel-shaped portion of a
conical bulb The lamp can be screwed info
an ordinary light socket or lamp base Lamps
with red or black glass faces absorb some of
the visible light, thus reducing the gbre’“
and, perhaps, also leading to some psycho-
logiatl benefits owing to the red glow that is
produced
The design of the heating element and the
reflector as well as their positioning relative
to one another markedly influence cover-
age pattern (i e , the pattern of the rays over
the treatment area at which they arc di-
rected) For example, faulty design may
cause undue concentration of the rays at a
smgle pomt, thus creating an undesirable hot
spot. Also, particular combinations of types
of heating elements and reflectors Wfill yield
coverage patterns better for some forms of
heat treatment than for others Catalog
desenpuons of infrared generators would be
much more meaningful if information about
the coverage pattern for each model were
given
Therapeutic Uses of Infrared. Irradiation
from both luminous and nonluminous sources
of heat rays produces marked hyperemia,
tissue relaxation and relief of pain Since the
effect of the difference m penetration of the
emanations appears to be of little practical
therapeutic importance, the nvo sources are
used interchangeably Radiant heating is used
to treat traumatic inffanunatory conditions
such as sprains and muscle strains, catarrhal
conditions of the mucous membranes and in-
fections of the skin includmg folliculitis and
furunculosis It is employed to relieve the
paxfl of vanous forms of arthntis and rheu-
matoid conditions as well as to relax and
warm muscles and tissues pnor to massage
and exercise Knowledge of the specific mctA-
anisms by which pam is relieved is incora-
pJete It can be sboivn that the threshold of
pain in a pcnphcral area of an extremity can
be raised by directly heating the sensory
nerve to the area •— The relaxing effect of
heat on skeletal muscle may ^ due to
ns effect on the neurons and the muscle
spindles mvolved m propnoceptor reflex
mechanisms
The technic of local radiant healing is quite
simple Radiation is directed over the part
to treated from a distance at which it feels
Infrared and Ultraviolet Generators 467
comfortable The average distance is from
2 to 3 feet If at any time the individual feels
an unpleasant bummg sensation, the heat
lamp should be moved farther away, a few
inches at a time, until he feels only a com-
fortable warmth The usual mtent is to cause
a reddening of the skm with a mmimum of
sweating, smce water absorbs infrared rays
Exposure generally is contmued for 20 to 40
minutes, but longer exposure is not harmful
m local treatment, provided that the radiation
is not too mtense Indeed, heat radiation
commonly is applied for too short a penod
to be effective Radiation should be di-
rected agamst noncovered surfaces, since
various textile materials absorb 20 to 40 per
cent of the infrared rays
The simple heat lamps available m phar-
macies are packaged with mstructions and
waramgs which the pharmacist should dis-
cuss with his client The major precautions
are du:ected toward the danger that the user
may be burned Blistenng may occur when
the radiation is too intense, the patient should
be warned that a severe bummg sensation is
not a part of the treatment. A burn may
occur when the circulation is poor because
of arterial disease, smce heat may not be
carried away from the area rapidly enough
Particular caution is needed m irradiating
anesthetic areas over skm scars or m cases
of nerve injunes, smce burning sensations arc
not fell and the tendency toward blistering
IS pronounced Blisters are more likely to
form if a strong Imiment has been applied
and has not been washed completely off
before beginning the heat treatment Con-
junctivitis and lens damage may occur fol-
lowing direct exposure of the eyes to infra-
red raj’s When irradiating the face, the eyes
may be protected with a shade or they may
be covered by pieces of absorbent cotton
moistened with rvater and flattened agamst
the eyelids Obviously, a hot lamp or cle-
ment should not be touched Some suggest
that all infrared lamps should have a guard
or a screen to catch hot broken glass or metal
chips m case of failure of the heating element
Short-wave diathermy and ulirasomc ther-
apy are also methods of applymg heat to the
body In diathenny, that region of the
body which is to be treated is posiuoned in
the field of an electrical apparatus which
generates a high-frequency current, com-
monly 27 12 or 35 7 megacycles per second
In ultrasomc treatments, the body is heated
through contact with an applicator contam-
mg a quartz or a barium titanate crystal
which IS made to vibrate through the piezo-
electnc effect at a frequency between 100
and 1,000 kilocycles per second Both meth-
ods mduce heat m deep tissues, that from
ultrasomc therapy tending to be more local-
ized These treatments are administered by
tramed physical therapists pursuant to a phy-
sician’s prescnption Pharmacists are not the
usual suppliers of these machines
Ultraviolet radiation (Table 93) is emitted
by very hot bodies and ionized gases The
sun IS the chief natural source of ultraviolet,
but sunlight reaching the earth contains none
of the short waves of the far ultraviolet, since
these are filtered out by the atmosphere
Artificial sources such as the carbon arc and
the mercury vapor arc have been developed
to assure independence from the vagaries of
the weather Pharmacists often supply ultra-
violet lamps for both lay and professional use
Effects of Ultraviolet I^ys. Numerous
physiologic actions have been claimed for
ultraviolet rays Local effects which may
occur in irradiated skin include erythema,
pigmentation, stimulation of growth of epi-
thelial cells and peeling Systemic activity of
Vitamm D may be observed followmg its
formation from 7-^ehydrocholesterol m the
skin Several other systemic effects of ultra-
violet irradiation have been noted.®® It is not
known whether the general tonic effect which
IS sometimes attnbuted to moderate exposure
to sunlight is psychological or actually de-
nved from some objective biochemical alter-
ation ®® Statements that colds are prevented,
mental activity stimulated and dental caries
prevented by ultraviolet radiation no longer
appear in advertisements for sunlamps
The local effects can be related to the
wavelength of the mcident radiation and the
layer of the skm to which it penetrates Eiy-
ihema is produced by wavelengths between
2,400 and 3,200 A, with two maximal areas
of eiythemal effecuveness approximately at
2,500 and 2,970 A The response is a
photochemical one in which absorption of
photons of ultraviolet eneigy by proteins or
nucleic acids or both causes the liberation of
468
Prescnption Accessories and Related {ferns
vasodilator and mflammatoiy substances not
yet identified The shorter waves are absorbed
in and affect the stratum comeum, the longer
waves act m the deeper stratum granulosura
The crjihcmal response is delayed from 4 to
8 hours, becoming visible sooner after a
strong dose than after a weak one Skin pig-
mentation or tanning follows repeated irradi-
ation with erythema producing doses between
2,800 and 3,000 A but not with those around
2,500 A The pigment consists of brown
granules of melanin which may appear in
irradiated skin m three ways An immediate
tanning effect, maximum m less than an hour,
IS due to a direct photo-oxidation of pre-
formed reduced melanin to darker, oxidized
melanin This results only with rays between
3,000 and 4,300 A A delayed tanning effect
which occurs several days after exposure con-
sists of an upward migration of mclanm gran-
ules from the melanocytes m the basal layer
A true darkening of the skin, beginning atout
two days after exposure, results from a syn-
thesis of new melanin stimulated by ery-
thema producing rays
It u well known that tanned sk/n shows
less erythcmal response than does untanned
The cryihema-producmg and the tanning rays
m some way stimulate epithelial cell division
which leads to a thicker stratum comeum
The increased thickness of the homy layer
IS believed to constitute the major protection
against further skin damage by irradiation
TTjc peeling which occur is the casting off
of dead cells, and its extent is proportional
to the degree of the erythema produced
Ultraviolet Lamps. The principal types of
artificial sources of ultraviolet radiation are
the carbon arc lamps and the mercury vapor
lamps For detailed descriptions of carbon
arc lamps which were the firet to be devel-
oped, but which have largely been replaced
by the more convenient forms of the mercury
vapor sources, see ScotL*^’
Passage of electric current through mer-
cury vapor causes the crmssion of ultraviolet
rays There arc three general types of mer-
cury vapor lamps, viz., the low pressure, the
high-prcssurc and the fluorescent. In all of
these types the mercury is enclosed in tubes
(bumcR) of fused quartz or of siLca glass,
because these materials transmit ultraviolet
freely and are, at the same time, extremely
heat resistant
The low-pressure lamp consists of an evac-
uated* quartz tube containmg a small amount
of liquid mercury and a small amount of neon
gas It has two electrodes which are con-
nected in senes with a stabilizing choke to
an alternating current transformer The dis-
charge IS mitiatcd in the neon This generates
enough heat to vaporize the mercury which
then takes over the carrying of the current
The discharge is earned by electrons and
positive ions The pressure is 0 001 to 0 01
atmospheres, the voltage is about 2,500 volts
and the spectral emission consists of about
95 per cent m the line of 2,537 A m the short
ultraviolet The tube remains cold because
very little current is consumed Lamps of this
type are used to treat superficial skin mfec-
tions and also to disinfect air, since bands
near 2,500 A have been shown to exert a
bactencidal effect They may be mounted on
reflectoR or incorporated in special holders
The Ji/g/i pressure lamp has an evacuated
quartz burner contaming traces of argon gas
and a larger amount of liquid mercury which
IS carefully adjusted to create a vapor pres-
sure of 2 to 10 atmospheres when fully
vaporized The electrodes are coated with a
theimiooic emitter (banum and strontium
oxides) to increase the supply of electrons
sufficiently to permit operating the tube with
a potential drop of about 100 volts A start
mg circuit which is actuated by pushing a
button momentarily applies about 600 volts
between an external electrode and one of the
intemal electrodes This initiates the argon
discharge The mercury arc is established in
2 or 3 minutes, but a total waiting period of
about 5 minutes is needed to allow it to sta-
bilize The operating current is 1 or 2 am-
peres, therefore, a lamp of this type gets quite
hot It IS generally cooled only by the room
air flowing around it A special type — the
Kromayer lamp — is equipped with a cooling
jacket m which water or air is circulated
The high pressure lamp emits radiant ene^
spread quite uniformly and widely through
the ultraviolet range For this reason, and,
also, because it can be made to emit higher
intensities than other types, the high pressure
lamp is the most used m clinical applica-
tions anti research The quartz burner
tends to deteriorate with use, being trans-
• If air were present mercury oxfdes would form
1
infrared and Ulfravjolet Generators 469
formed gradually by heat to tndymite, an
ultraviolet-opaque form of silica Rheostats
arc generally provided to allow mcreased
voltage to be used as needed to restore the
output of rays After several hundred hours
of use the bulbs may need to be replaced
The burner should not be touched with the
fingers because the finger marks will become
permanently etched into the quartz when the
burner is heated agam If it is touched mad-
vertently, the burner should be cleaned im
mediately with ethanol
The fluorescent tube operates on the same
prmciple as the fluorescent tube used for
lightmg It IS a modified low pressure mer-
cury arc tube which is coated with a special
fluorescent phosphor on its mner wall The
arc, operatmg at 0 00001 atmospheres pres-
sure, emits radiation at 2,537 A This is ab-
sorbed by the phosphor which then emits
radiation of longer wavelength, mostly near
3,000 A The glass used is one which absorbs
rays shorter than 2,800 A These tubes may
be 3 to 4 feet long and are mtended for gen-
eral body irradiation
Sunlamps have been developed for home
use as a source of radiation similar to sun-
light These are special glass bulbs which are
opaque to wavelengths below 2,800 A and
are similar m shape to ordinary electric light
bulbs There are three types, the S-1, the S 2,
and the RS The RS (reflector) type is the
one commonly stocked by pharmacies, since
11 can be screwed mto ordmaiy sockets and
operates at 110 to 125 volts, whereas the
others require a special fixture with a trans-
former Tlie RS bulb is comcal and has an
aluminum coatmg on the funnel-shaped por-
tion to act as a reflector Inside the outer ^ass
envelope is a small high pressure mercury-
arc tube made of quartz There is a tungsten
filament which heats up to vaporize the mer-
cury and then remains in the circuit as a
ballast ’ Because of this incandescent fila
meat the RS bulb enmts radiation in the visi-
ble and the short infrared portions of the
spectrum as well as m the ultraviolet
Ultraviolet Therapy Techmc. The techmc
of applying ultraviolet radiation is an exact-
ing one, inasmuch as it is necessary to regu-
late closely the duration and the frequency
of the applications as well as to control the
intensity of the radiation by adjustmg the
distance of the burner from the patient Only
relatively nonspecific mstructions can be
given, since the details will vary according
to the efficiency of the apparatus, the mdi-
vidual sensitivity of the patient and the prog-
ress of the treatment For general (over-
all) body irradiation the first dose is one
which barely causes a first-degree erythema
Patients develop increasing tolerance as treat-
ments contmue and become able to stand suc-
cessively larger doses The burner is usually
placed about 30 mches from the mdividual
at first and the begmnmg exposure tune may
be only 15 seconds Treatment is not repeated
until the erythema response from the previous
exposure has completely subsided This lunits
frequency of application to every other day
or to once daily at most After the mitial ex-
posure It IS usual to leave the burner at the
same distance and to mcrease the tune by,
perhaps, IS seconds each tune until the ex-
posure lime becomes about 3 minutes (or
less, depcndmg on the equipment) Some ch-
nicians then move the burner closer to the
individual m 2 inch progressions down to a
minimum distance of 1 8 inches
There is a wide range in individual sensi-
tivity to ultraviolet *** Blondes are from 40
per cent to 170 per cent more sensitive than
brunettes, men are 20 per cent more sensitive
than women Even different body areas react
differently to radiation, those with a thick
homy layer are the least sensitive, and the
face is the most sensitive
Efficiency of ultraviolet generators is meas-
ured by the degree of erythema produced
under standard conditions of exposure This
cntenon was adopted by the Amencan Medi-
cal Association’s Council of Physical Medi-
cmc® when it was issuing seals of acceptance
for brands of various devices, a practice dis-
contmued m 1955 Four degrees of ery-
thema are recognized First-degree erythema
IS a slight reddening of the skin which fades
within 24 hours In second-degree erythema
the reddening is more pronoun^ and it lasts
about 3 days, it is equal to a mild sunburn
Thud degree erythema is similar to a severe
sunburn, smce the reddening is intense and
there is some edema and peeling of the skin
It takes about a week to subside Fourth-
degree erythema follows destructive doses,
which, after a short latent penod, produce an
intense reddening followed by exudation and
blistering This persists for many days The
470 Prescription Accessories and Related
Table 94 Possible Photosensitizers
(Oral or Injected)*
Thiazide diuretics
Carbonic anhydrase
Sulfonamides
inhibitors
Tolbutamide
Antibiotics
Quinine
Demethylchlor-
Methylene Blue
tetracycline
Chlortetracycline
Endoennes
Griseofulvm
Imulin
Adrenalin
Phenolhiazines
Pituitnn
Chlorpromazine
Thyroid
Promazine
Promethazine
Heavy metal salts
TnJJupromazjne
Mercury
Iron
Methoxsalen
Bismuth
Barbiturates
Gold
Salicylates
Silver
Para aminobeozoic
acid
* Data from Med Letter 3 56 1961. Watkins
ALA Manual of Electrotberapy, p 80, PbiU
delphia. Lea * Febiger, 19SS
Council* ** adopted an erythemal unit of
dosage intensity svhich was based on the in*
tensity of radiation of wavelength 2,967 A
capable of producing a mmunutn perceptible
erjthema on average untanned skin m 15
minutes Then, artificial sources were rated
in terms of the number of erythemal units
they should produce if they were elTiciently
designed The Council also distinguished be-
tween two general types, i c , sudamps and
therapeutic lamps Sunlamps were chose emit-
ting ultraviolet radiation almost entirely be-
tween 2,900 and 3,132 A, these were con-
sidered to be safe for unsupervised use
Therapeutic lamps are intended for profes-
sional use only or for patient use under the
direction of a physician Types S-I, S-2, RS
and fluorescent types are sunlamps High-
pressure lamps and also some low-pressure
ones are classed as therapeutic
Dangers of Ultraviolet Radiation. The dan-
gers in home use of ultraviolet are obviously
manifold The pharmacist who supplies de-
vices for this purpose must volunteer the
necessary precautionary statements even
though they may seem to be expressed clearly
m instructions acaimpanying the device He
should warn against overdose from either a
single excessive exposure or from too fre-
quent exposure Some mdmduals have an
exaggerated idea of what they can withstand
and tiy to get a deep tan in one sitting Others
simply fall asleep under the lamp This is a
major reason for stocking lamps with timers
that can be set to shut oS the lamp auto-
matically Lamps should not be touched,
since they are hot enough to bum That the
eyes can be damaged by ultraviolcl is com-
monly known Wavelengths below 3,200 A
arc responsible Conjunctivitis and blephantis
with a painful pricking sensation may de-
velop after bnef exposure Edema, contrac-
tion of lids and comeal erosion may occur
Long exposure to intense ultraviolet rays
may produce color scotomas, constnction of
the peripheral field and, some believe, lenticu-
lar cataracts Consequently, protective goggles
widi dark smoked lenses should be worn by
the user Several serious forms of dermatitis,
general toxemias, exacerbation of tuberculosis
and precanccrous skin lesions may result
from excessive or incorrect use of ultraviolet
radiation Some authorities feel that the
dangers of home treatment with ultraviolet
radiation outweigh possible benefits ***
The phamaetsc has a special responst-
bility, because the use of certain drugs is
known to cause an increased sensitivity to
ultraviolet rays The photosensitivity reaction
may be phototoxic or photoallcigic or both “
The phototoxic reaction resembles a severe
sunburn, and residual tannmg appears after
the erythema subsides PhotoaUergic re-
sponses, which result from an antigen-aati-
Iwdy rcacuon, require an incubation period
of several days following exposure to both
the drug and ultraviolet for the sensitization
to be developed Subsequent exposure to
ultraviolet may develop the reaction — ^usually
a severe urticarial dermatitis — withm a few
minutes There is no residual tanning Even
a partial luting of drugs implicated as phoio-
sensitizcrs (Table 94) is impressive evidence
of the need for caution Coal tar prepara
Dons require special mention as being photo-
sensitizcrs when applied cxtcmally Thephar-
macut who supplies a sunlamp for home use
should certainly be informed of the drugs
which the intended user u tabng so that sen-
sitization reactions may be avoided
References 471
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recalcitrant urinary tract infections, J
Arkansas Med Soc 52 271, 1956
87 Little, L D , and Wise, R A , General
Electric Co , Asheboro, N Carolina
Personal communication
88 Lockie, L D Medicinal Adjuncts and
Home Remedies p 7, Buffalo, U of
Buffalo, School of Pharmacy, Undated
89 Lormcz, A L. Physiological and patho-
logical changes m skin from sunburn and
suntan, J,A M A 173 nil, 1960
90 Lyght, CE,ed Merck Manual, ed 10,
pp 415, 1756, 1302, Rahway, Merck,
Sharp and Dohme, 1961
91 Lyman, R A , ed Araencan Phaimaqr,
Vol 2, pp 286, 308, 314, Philadelphia,
Lippincott, 1947
92 Lynch, M J , and Gross, H M Arti-
ficial sweetening of liquid pbarmaceu
ticals, Drug & Cosmetic Ind 87 324,
1960
93 MacLeod, J , Sobrero, A J , and Inglis,
W In vitro assessment of commercial
contraceptive jellies and creams, J
176 427, 1961
94 McNamara, R 3 , Farbcr, E. M , and
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1066, 1959
95 Martin, E W , Ed lo-chief Remington’s
Practice of Pharmacy, ed 12, pp 1546,
1556, 1560, 1660, 1661, Easton, Mack.
1961
96 Mehoert, J H Broken thermometer bulb
penetrating the submaxiUary duct. Am J
Surg 98 743, 1959
97 Methods of Contraception in the United
States, New York, Planned Parenthood
Federation of America, Inc , 1961
98 Model!, W , ed Drugs of Choice, 1962-
63, pp 475, 498, Saint Louis, Mosby,
1962
99 Modern Medical Methods for the Control
of Contraception, pp 17-21, Rantan,
N J , Ortho Pharmaceutical Corporation,
1961
100 Montag, M L, and Swenson, R P S •
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pp 316, 318, 371, Philadelphia, Saimders,
1959
101 Munch, J C Pressor Drugs III Safety
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(Sci ) 44 208, 1955
102 Munch, J C , Sloane, A B , and Latven,
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1951
103 Murphy, D J , and Femckes, R J , Casco
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104 Musselman, M M , Cosand, M R , and
McFadden, W H , Jr to be published
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Hosp Topics iP 87, 1961
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1953
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1955
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C/iopfer 13
Hospital Pharmacy
George F. Archomboult, Ph C , LI B , LL D , Sc D , Pharm D *
Hospital pharmacy, or, more properly,
pharmaceutical service m hospitals, is a rela-
tively new specialty m the profession of phar-
macy It IS one that has matured since the
twenties as a result of improvements m the
standards of hospital care and developments
m the present-day drug armamentanura
Definition. Hospital pharmacy is that spe-
cialty of pharmacy that concerns itself with
the evaluation, the selection the procure-
ment, the storage, the control and the utili-
zation of drugs m hospitals It encompasses
the supplymg of medications for inpatient
and outpatient use, the preparation of stenlc
medications, volume compounding, prepack-
aging, drug formulation and research Fur-
thermore, hospital pharmacy serves as the
focal point m the dissemination of drug-
thempy information to the staff
HISTORY
The separation of pharmacy from medicine
first look place in the early eleemosynary in
stitutions engaged in caring for the sick and
the injured History records the faa that
* Pbannacy Uauon OlRcer to the Office of the
Surgeon General Chief Pharmacy Branch Di
vision of Hospilals, U S. Public Healib Service
Department of ficalth Education and Welfare
U ashington. D C
This chapter has been prepared with the thought
in mmd of familiarizing the student with the basic
concepts ot the practice of hospital pharmacy ad
ministration In general the chapter folloi^'s the
proposed syllabus for a coune on hospital pbar
macy administraiion as presented by the special
Committee on Education of the Amencan Swiety
of Hospital Pharmacists (See EducaUon and In
temship number Butl Am Soc Uosp Pharmaehts
May June 1955 )
pharmacies were important segments of hos-
pital activities as long ago as the 4th century,
at a time when hospitals were part of many
of the monastenes After the plague m the
I4ih ccnluty, the separation of pharmacy
from medicine became an established fact,
and hospitals of that era are reported to
have had well-equipped phannaceutical
services
The first hospital pharmacist m colonial
America is believed to have been Jonathan
Roberts, pharmacist of the Pennsylvania Hos-
pital m Philadelphia (1752) (Fig 167)
Benjamin Franklin, who aided m the es-
tablishment of this hospital, wrote
The practitioners charitably supplied the
medicine gratis till December. 1752 when the
managers, having procured an assortment of
drugs from London, opened an apothecary s
shop in the hospital, and it being found neces
sary, apjxiinted an apothecary to attend and
nuke up (he medicines daily, according to the
prescnplion with an allowance of fifteen
pounds per annum for his care and trouble
he giving bond with two suflicicnt sureties for
the faithful performance of his trust
Prior to 1920 for a penod of approxi-
mately 170 years, the recorded history of
hospital pharmacy in the United States is
quite brief The majority of pharmacists en-
gaged m this specialty of the profession re-
ported little m the literature and received
little recorded recognition from American
pharmacy
Not until the Amcncan College of Sur-
geons began Its hospital standardization pro-
gram in 1918 was there any notable change
m this apathy
Starting in the early twenties and contmu-
mg strongly thereafter, hospital pharmacy
Atnencan Society of Hospifol Phormacis^s 477
Fjo 167 Picturizalion of the first hospital pharmacy m Colonial America (c 1755)
(Copyright 1954, Parke Davis and Co )
began to attract attention as an important tional groups for the betterment of patient
element m hospital patient care Three fac care
tors might be named as contributing greatly
to the present vigorous activity of the prac AMERICAN SOCIETY OF HOSPITAL
tice of hospital pharmacy the standardiza PHARMACISTS
tion program of the Atnencan College of
Surgeons (now the program of the Joint The national society for hospital pharma
C^ommission on Accreditation of Hospitals) cists was founded m 1942 and incorporated
to upgrade patient care m hospitals, Uic de m 1955 The society, an affiliate of the Amer
velopment since 1940 of the powerful drug ican Pharmaceutical Associauon is devoted
annamentanum available to the medical prac to the profession of hospital pharmacy and
litioner of today an armamentarium that nc dedicated to the unprovernent of pharmaccu-
cessilates highly tramed pharmacists to guar tical service m the mterest of better pauent
antee the proper selection control and use care m hospitals Over 3 000 hospital phar
of drugs, and the influence of the Amen macy pracuuoners hold membefship m this
can S«iety of Hospital Pharmacists This organization, many belongmg to one of the
nationalsocietyworkscloselywiththeAmen 57 affihatmg local chapters The journal of
can Pharmaceutical Association, the Ameri- the society, American Journal of Hospital
can Hospital AssociaUon the Catholic Hos Phannacy, is well known mternaUonally in
pita! Association the Joint Commission on hospital and pharmaceutical circles
Accreditation of Hospitals and other na- 1)16 objectives of the Amencan Society of
47S Hospital Phormacy
Hospital Phannacjsts as stated in the consti-
tuiUon and bylaws (1962 revision) arc
The objectives of the Society shall be (1) to
provide the benelits and protection of a hospital
pharmacist to the patient, to the institution
which he serves, to the members of the allied
health professions with whom he is associated,
and to the profession of pharmacy (2) to assist
m providing an adequate supply of such quali
fied hospital pharmacists (3) to assure a high
quality of professional practice through the
establishment and maintenance of standards,
(4) to promote research in hospital pharmacy
practices and m the pharmaceutical sciences
in general (S) to disseminate pharmaceutical
knowledge by providing for interchange of in
formation among hospital pharmacists and
members of allied specialties and professions
VITAL STATISTICS ON HOSPITAL
PHARMACY IN THE UNITED STATES
Hospital pharmacy in the United States is
a recognized specialty of the profession of
pharmacy and a valued service ta sound hos-
pital operations Statistics reQect this oosi-
tion. For instance over 53 per cent ot the
6,712 hospitals reporting in the 1962 listing
of the American Hospital Association state
that they operate pharmacies
RESPONSIBILITIES AND DUTIES OF
THE HOSPITAL PHARMACIST
The responsibiliUcs of the hospital phar-
macist are set forth clearly m the Minimum
Standard for Pharmacies in Hospitals of the
American Society of Hospital Pharmacists
as amended November 8, 1962 These duties
are slated to be as follows
The preparation and sterilization of inject
able medications when manufactured in the
hospital, the volume compounding of pharma
ceuticah, the manufacturing of pharmaceuli
cals, the dispensing of drugs, chemicals and
pharmaceutical preparations, the filling and
labeling of all drug containers issued to services
from which'medication is to be administered
necessary inspection of all pharmaceutical sup-
plies on alt services and at nursing medication
stations the maintenance of an approved stock
of antidotes and other emergency drugs, the
dispensing of all narcotics hypnotics, and alco-
hol and the maintenance of a perpetual inven
lory ot them, the development of specifications
both as to quality and source for the purchase
of an drugs, chemicals, antibiotics, biologicals,
and pharmaceutical preparations used in the
diagnosis and treatment of patients, furmshing
information concerning medications to phy-
sicians. interns and nurses, the establishment
and maintenance, in cooperation with the ac-
counting department, of a satisfactory system
of records and bookkeeping in accordance with
the policies of the hospitd for (a) charging
patients for drugs and pharmaceutic^ supplies,
and (b) maiaUimog adequate control over the
requisitioning and dispensing of all drugs and
pharmaceutical supplies, the planning, organiz-
ing, and directing pharmacy policies and pro-
c^ures in accordance with the established poli-
cies of the hospital, the maintenance of the
facilities of the department, cooperation in
teaching counes to students in the school of
nursing and in the medical and dental intern
training programs, implementing the decisions
of the pharmacy and therapeutics ajnunittee
and serving as secretary to the committee, and
the preparation of periodic reports on the prog-
ress of the department for submission to the
administrator of the hospital
To (he Admimstralion. Directly or mdi-
rectly, these rcspoosibilities and functions are
aunra to provide the best m pharmaceutical
service for the patient at the most economical
c£»L Not only is it the duty of (he hospital
pharmacist to provide good pharmaceutical
semee to the patient, it is also his responsi-
bility to operate the pharmacy department
effiaently and economically This the com-
petent pharmacist does by providing quality
medications and services at the most favor-
able prevailing pnccs
To ibe Clinicians. It is often said that the
hospital pharmacist is the drug therapy con-
sultant to the staff, this is one of his prime
responsibilities He continuously must be alert
to the latest trends m clinical pharmacology,
biochemistry, microbiology and the other
health sciences He must be prepared to dis-
cuss With clinicians the relative ments of
drugs and to advise on their dosage, strength,
side effects, contramdications, use and oUier
pertinent factors
To the Nursing Profession and Paramedi-
cal Groups. The hospital pharmacist has pro-
fessional responsibilities to the nurse, the
dietitian and the medical record librarian In
j
Responsibilihes and Duties of the Hospital Pharmacist 479
hjs penodic inspections of nursing medica-
tion stations he should be alert to prevent
labeling and packaging by nursing personnel,
detect outdated biologicals and ampul medi-
cations, spot excess and obsolete stocks as
well as check on narcotic and hypnotic vicda-
tions The competent hospital pharmacist ful-
fills his teachmg responsibilities by lectures
to nurses and others on the action and the
uses of drugs and their side effects and con-
traindications, and on pharmaceutical arith-
metic, posolo^ and toxicology It should go
without saying that the preparation of anti-
biotic suspensions, surgical fluids and paren-
terals falls into ha domain and not that of
the nune
The hospital pharmacist's responsibilities
to the dietetic department hes m his knowl-
edge of vitamms, essential ammo acids, min-
eral and other food supplements He can best
advise as to the preparations to be stocked
to obtain the greatest value per dollar ex-
penditure Also, his skill m preparmg elegant
fla\mnng extracts for hospit^ consumption is
brought to bear m this relationship
To ti\e medical record hbianan, as well as
to the nurse and the medical and the dental
mtem, the hospital pharmacist has the re-
sponsibility to teach, among other thmgs, sci-
entific drug nomenclature and the generic
names of drugs, as well as their many trade
names
To the Department. To the pharmacy
Itself, the hospital pharmacist is responsible,
of course, for adequate mventones of quality
drugs, the periodic inspection of equipment
and Its maintenance, the general appearance
of the department, the standardization of
medication contamers for pharmaity and
nursmg station dispensmg umts, and the giv-
mg of prompt, efficient service
Also, under this bnef discussion of re-
sponsibilities should be mentioned the ne-
cessity for adopting a policy relative to
Fig 168 The pharmacy service m relation to the administrator and
to all other departmental services of the “X ’ Hospital (Developed by
Mr Ray Kneifl, Sister Mary Berenice and others for the Catholic Hos-
pital Association in conneclioo with the Point Ratmg Plan for Hos-
pital Pharmacy Service m the Bulieiin of the Amencan Society of
Hospital Pharmacists, 9 No 4)
Organixatton and Policies 481
Sample Outline of Policy or Objective
Statement*
In the development and conduct of the Phar
macy Service (Department) of
Hospital, jt shall be the primary purpose of the
Sisters of , their associates and
assistants m this department, to render efficient
professional service motivated at all times by
Chnstian chanty to in- and out-patients of aU
economic levels, to this end, the chief pharma
cist and staff pharmacists wQI cooperate whole-
heartedly with medical staff members, and espe
cially with the Pharmacy and Therapeutics
Committee, in the development of sound poli-
cies governing this service The program of
service shall include
To achieve the desired measure of efficiency
throughout the hospital, this department will at
all times cooperate with other special depart
ments m Hospital har
moniously and effectively to assure continuity
of service to patients, providing the education^
guidance and matenals relating to scientific ad
vances m drug therapy for other professional
groups as well as for pharmacists The Phar
macist will cooperate with the Director of the
School of Nursing in her teaching program for
student nurses
In realixmg this goal the administrator of
the hospital and the chief pharmacist are guided
by the “Minimum Standard for Hospital Phar
macies” of the American Society of Hospital
Pharmacists In the organization, staffing, equip-
ment and admmistration of the pharmacy In
complymg with the Standard the Pharmacy
Service of Hospital attempts
to qualify for recognition by appropriate ac
crediting agencies m Medici, Pharmacy and
hospital fields as providing a service of profes-
sional quality adequate to safeguard the health
of the people
(Paragraphs may be added or developed for
special services (functions) if desired )
Pharmacy and Therapeutics Committee
The Minunum Standard for Pharmacies tn
Hospitals m reference to the Pharmacy and
Therapeutics Committee states
Pharmacy and Therapeutics Committee
There shall be a Pharmacy and Therapeutics
Committee, which shall hold at least two regu
lar meetings annually and such additional meet
mgs as may be required The members of the
• Prepared by Mr Ray Kneifl, Sisler Mary
Berenice and associates, Catholic Hospital Assoa
ation. Institute on Hospital Pharmacy, July, 1952
committee shall be chosen from the several divi
sions of the medical staff The pharmacist in
charge shall be a member of the committee and
shall serve as its secretary He shall keep a trans
script of proceedings and shall forward a copy
to the proper govemmg authority of the bos
pital TTie purpose of the committee shall be
(A) to develop a formulary of accepted drugs
for use m the hospital, (B) to serve as an ad-
visory group to the hospital pharmacist on mat-
ters pertaming to the choice of drugs to be
stocked, (C) to evaluate clmical data concern-
ing dru^ requested for use in the hospital, (D)
to add to and to delete from the list of drugs
accepted for use in the hospital, (E) to prevent
unnecessary duplication in the stock of the same
baste drug and its preparations and (F) to make
recommendations concerning drugs to be
stocked on the nursing units and other services
To this role, another important item has
been added recently — the penodic review of
patient's charts for mconsistencies m medi-
cation orders (ovennedication m number of
drugs used and use of a drug beyond a rea-
sonable period) with report on findings made
at least once annually at staff meetings
Names of patients and physicians are, of
course, oot revealed
The role of the chief pharmacist on this
committee, as its recorder or secretary and
as one of its votmg members, is an important
one Among the more important functions
are
1 Maintenance of an adequate, up-to-date
library and a drug therapy reference file for
the use of the committee and the staff
2 Interviewing and screening of profes
sional medical representauves ( detail men”)
of pharmaceutical firms, and arrangmg for
departmental mterviews with them when in-
dicated This IS an important function of the
secretary masmuch as it keeps him mfonned
of the latest drug therapy agents bemg de-
tailed by the pharmaceutical firms to phy-
sicians on the staff, either at the hospital or
m their offices This function is admmistra-
tively valuable to the hospital m that it con-
serves the tune of staff members without the
loss of the valuable information that the de-
tail representatives have for members of the
vanous services
Arrangmg vnlh the detail representative
for the presentation of exhibits to the staff at
optimum times At such meetings, the detail
representative of a pharmaceuticd firm has
482 Hespilal Pharmocy
the opportunity to discuss the pharmacology,
the biochemistry, the microbiology or ie
pharmacy of his product wth all interested
staff members
3 (a) Prompt preparation and disscmma-
Uon of accurate minutes of committee activi-
ties This rcsponsibiliQ' caimot be emphasized
too strongly The proper custody of the min-
utes is equally important The surveyor for
the Joint Commission on Accreditation of
Hospitals may ask to inspect the record of
pharmacy committee meetings In evaluating
the hospital pharmacy, the inspector con-
siders the recorded activities of the pharmacy
committee as well as the hospital formulary
(b) Seeing that the minutes of the commit-
tee and the format of the formulary arc more
than a mere recording of decisions to add
and delete drugs and a list of drugs currently
stocked The mmutes should contam the
pharmacologic basis for a drug s selection or
rejection The formulary should contam a
format on each drug comisting of its generic
or oiBctal name, all important trade names.
Its identifymg characteristics, actions, contra
indications, side effects, toxicology, posology,
size and strengths available
4 Preparation of the agenda for each
meetmg after approval by the chairman and
releasing it to committee members sufBctenily
m advance of the meeting to allow time for
intelligent preparation
5 Editing of the formulary (after review
by all pharmacy committee members and
final review and approval by the medical and
the dental staffs), as well as mainiaimng cus-
tody of and issuance of formulary and sup-
plements to medical staff members, residents,
interns and other authorized personnel such
as nurses and medical record librarians
6 Encouraging of individual staff mem-
bers to present requests for drup to the com-
mittee, and assisting of staff members to col-
lect proper and adequate information to cover
the request (see Fig 170)
7 &rvmg as a drug therapy consultant to
the staff, especially the residents, the interns
and the nurses These services usually ore
given m private conferences, but much value
IS obtained from formal lectures to medical
and dental interns and the nursing staff
Also, as a voting member on this commit-
tee, the pharmacist must
1 Prepare himself by sufilcient study to
mtelligently discuss and participate m making
decisions on the subjects placed on the agenda
for consideration
2 Attend all meetiop regularly and
promptly
3 Place the medical needs of the patients
and the hospital above his personal scientific
interests and desues m mal^g recommenda-
tions and decisions
4 Dlsscmmatc the committee’s thinkmg
and aims among his colleagues as well as
bnng his colleagues’ problems and thinking
to the attention of the committee
5 Stress the use of generic and official
names when workmg with the staff or the
teaching residents the interns, the nurses and
the mescal record libranans
6 Favor the policy of using “blind tests”
m controversial areas In other words, drup
to be studied should be so labeled that only
the chairman and the secretary of the com-
mittee know the exact identi^ of a drug until
the committee has had time to evaluate all
the clinical and pharmacolopc evidence pre-
sented to IL
7 Keep himself appraised not only of the
pharmacologic merits of drup but also of
their comparative costs in relation to their
efficacy
8 Weigh his decisions not only m the Lght
of providmg the best drug therapy for patients
but also of preventing needless and wasteful
duplication m the same class of drugs
9 Work for the establishment of mean-
mgful drug terminology Discourage unsafe
practices m drug identification such as the use
of synonyms, codes, numbers or letters, and
the use of trade names without knowledge of
the generic or the official name, also promote
and advocate the use of the metric system in
svard prescribing, nursing station medication
labeling and formulanes
10 Advocate and work for the establish-
ment of Restricted Drug Lists Because of
tbcir complex action, potency and toxicity,
certain modern-day drop, in the mterest of
better patient care should be restneted to use
by those staff members wth special com-
petency m their administration
THE HOSPITAL FORMULARY
A formulary has the following purposes
and goals
PKS 1689
KEY 6-S5
REQUEST rOR NON BASIC DRUB
HOSPITAL OR CLINIC
TO PHARMACY COMMITTEE UirtaEti Cbief Pbsrnuist
NAME OF MANUFACTURER
DOSAGE FORM WANTED (Check one)
□ TABLn □ CAPSULE
□ AMPULE □ OTHER (Spec fr)
□ LIQUID □ OINTMENT
□ POWDER
MINIMUM SUPPLY REQUESTED
1 □ ROUTINE
□ EMERGENCY
NAME OF PATIENT DR SERVICE FOR WHOM DRUG IS REQUIRED
DESCRIBE PHARMACOLOCICAL ACTION NEEDEO
IS THERE A SIMIUR ACTING DRUG STOCKED IN THE PHARMACY WHICH MAT BE USED!
O NO □ YES (If TES what advantags does Ih s drag
have’)
Remarks
HH.'!.Uil:Hiia^ltilWfil:1.10fJT>ltAI I H 1 1 1 1 1|| 1 j
1 PHARMACEUTICAL SERVICE REPORT ON DRUG
MnsTuimnuui
(Bst of drug
1 COST OF SIMIUR ACTING ITEM STOCKED
REMARKS
SIGNATURE OF CHIEF PHARMACEUTICAL SERVICE | DATE
^ PHARMACY COUUlIUl REPORT
DRUG □ APPROVED □ REJECTED
REASONS
PHARMACY COMMinEE RECORDER (S gnatu t)
Fiq 170 Request for nonbasic drug to pharmacy committee through the chief phar
macisu (U;S P )
484 Hospital Pharmoqr
1 To provide the patient with the best
possible drug therapy
2 To provide the physician and the den-
tist with carefully selected agents of proved
effectiveness, which will be a basis for flexible
drug therapy
3 To provide a standard of companson
for the evaluation of new therapeutic agents
4 To provide the physician, the dentist,
the pharmacist and the nurse with a ready
reference on the essential pharmacolo^ of
the basic drugs
5 To provide for simplification of all
drug therapy record keeping
Pharmacy and therapeutic committees are
now in operation in many of the nation’s hos-
pitals These committees have indtviduaQy
developed entena for the evaluation of drugs
Essentially, these criteria all aim at selecting
for the formularies of the hospitals the best
among approximately 2,500 available drug-
therapy agents Critena used by many com
mittees are as follows
1 The therapeutic efficacy of the drug
should be v.cll established
2 Preference should be given to USP
N F , D and ADR drugs
3 Unnecessary duplication of action
should be avoided
4 Drugs of secret composition should be
rejected
5 Unless they provide a real advantage in
combination form, mixtures of drugs should
be avoided
Formularies should be revised periodically
or be loose leaf manuals that can be kept
uijto-datnb^sbnetoejlancconnfi Thattsitoif
the formulary system should never be so rc-
stnctive as to prevent the physician from ob
taming any desired drug in an emergency
The use of the formulary system has many
advantages Foremost, of course, is the bring-
ing to the patient those drug-therapy agents
considered b) the committee to be the best
available Other advantages are reduction m
mventones and m the number of ordere
processed This is brought about by the
elimination of many duplications m basic
drugs The formulary is a valuable reference
for the staff, especially the busy intern and
resident, as to the drugs slocked by the phar-
macy, their preparations, strengths, forms,
dosage and dispensing sizes
It cannot be stated too strongly that the
formulary of a hospital and the use of the
formulary sj-stem is a medical staff responsi-
bility and not a function or a responsibility
of the hospital administrator or pharmacist
These individuals implement the sj’stem and
the decisions of the Pharmacy Committee
as ratified by the medical staff as a whole
Further, “cunent” or “present” consent of
the prescriber is mvolved in the dispensmg
of a nonpropnetary medication irrespective
of whether it is or is not of the same brand
referred to in the prescnption or medication
order For the leg^ protection of the phar-
macist and the hospital, all medication con-
tainers dispensed under the formulary system
should carry the strip label approved by the
American Hospital Association and the
American Society of Hospital Pharmacists
and reproduced tielow
Further, prescription order forms and patient
progress or medication charts should carry
the following footnote “O Authorization is
given for dispensmg by nonpropnetary name
unless checked here ”
It must be borne m mind by hospital phar-
macists and administrators, relative to the
Formulary System Concept, that this is an
accepted and approved method whereby the
wedic-it stag ot wQtV;w.g
a Pharmacy and Therapeutics Committee
selected by u evaluates, appraises and selects
from among the various medicinal agents
available those that arc considered to be most
useful m patient care, together with the phar-
maceutical preparations in which they may
be administered most effectively
Five-Poivt Statement of Operation
FOR THE Hospital Formulary System
(Adopted May 1963 by the American So-
aety of Hospital Pharmacists, the Ameri-
can Pharmaceutical Association, the Amen-
Personnel
485
can Hospital Association and the Amencan
Medical Association *)
To promote the adoption of a Fonnulary
System by the hospital medical staff with the
understandmg that the admimstratioa of such
a program will
1 Be mitiated and operated withm the indi-
vidual hospital through regulations promulgated
by Us medical staff
2 Insure the maintenance of the responsi
bihty and prerogatives of the physician m the
exercise of his profewional judgment.
3 Provide for final determination by phy-
sicians and pharmacists of medications to ^
included m the formulary
4 Authorize the physician to preacnbe medi-
cations not included m the fonnulary if m hts
judgment individual patients require special
treatment and
5 Permit the physician, at the time of pre
scnbing medications, to approve or disapprove
the dispensmg or administrauon of medications
m accordance with the Hospital Formulary
System
PERSONNEL
Agam referruig to the Minimum Stand
ard, It IS noted
Pefiooael. The pharmacist m charge shall be
well trained in the specialized functions of ho$
pital pharmacy and shall be a graduate of an
accredited college of pharmacy or meet an
equivalent standard of training and experience
as set forth in the supplement to these stand
ards He shall have such assistants as the volume
of work in the pharmacy may dictate These
assistants shall include an adequate number of
additional registered pharmacists and such other
personnel as the activities of the pharmacy may
require to supply phannaceutical service of the
highest quality All members of the staff of the
pharma^ shall be competent, of good moral
character and mentally and physically fit to per
form their duties acceptably
Specifically, the properly qualified hospital
pharmacist should be well versed m his
knowledge of medications and their actions
mcluding side effects and contraindications,
* To guide hospital pharmacists physictaos ad
miRistralors and others as to the intent of this Five
point statement, a Statement of Guiding Pnsciples
on the operation of the Hospital Formulary Sy%
tern is currently (June 1963) under development
by the four national groups concerned
Table 95 Pharmacy Personnel*
Staffing Pattern^
Bed CAPAcriYt
50
100 200 500 750 1,000
Chief
It
1
1 1
1
1
Assistant chief
0
0
1 1
1
2
Staff pharmacist
0
0
0 1
2
1
Intern
0
0
1 2
2
3
Secretary-
stenographer
0
0
0 I
I
1
Cashier§
0
0
0 1
1
1
Pharmaiy helper-
stock control
clerk
0
0
0 1
1
1
Pharmacy helper
0
1
1 1
2
2
• Based on outpatient activity of approximately
70 prescriptions daily
t Add 1 additional pharmacist for each addt
tionai 70 individual outpatient prescnptions dis
pensed daily above basic 70 If prepackaging is in
effect, ratio is higher
t Assumes 1 or more additional areas of super
vjsion—x ray service, central stenie supply. labora
lory, purchase and supply activities, general admin
istratioQ
$ If oulpaueat activity and hospital poLcy indi
cate
^ Based on normal workloads, meludmg the fol
lowing measurable and nonmeasurable factors
1 Compounding and dispensing of individual
outpatient prescnptions
2 Ward and cLmc (basket) issues
3 Hospital manufactured pharmaceuticals
4 Time consumed in individual consultations
With medical dental and other staff members on
drug therapy problems
5 Teacbng schedules — medical dental, phar-
macy iDieras nurses, medical record Iibranans
6 Preparation of extemporaneous sfenle paren
teral and surgical solutions of narcotics antibiotics
etc
7 Requisitioning and/or purchasing of supplies
8 Maintenance of perpetual inventories
9 Preparation of reports monthly, annual, on
stock control of inventones, drug costs, workloads
10 Attendance at and participation m staff phar
macy committee and other meetings
1 1 Clinical pharmaceutical research
12 Indoctrination and traimng of department
personnel
he should have the ability to develop and
conduct a pharmaceutical bulk-compounding
program, he should have mtimate knowledge
of control procedures including technics to
ensure quality control and distribution con-
trol He also must have the ability to conduct
486 Hojpilcl Pharmacy
and participate m research, teaching and m-
servicc training programs Finally, be must
have the abiLty to administer and manage a
pharmacy service in a hospital that devotes
Itself to patient care, research and teaching
Proper manpower m terms of quantity and
quality is necessary m operating any of
service Sound personnel practice requires
that the personnel office recruit for specific
vacancies, screen out those applicants who
manifestly do not meet the requirements of
the proposed position, and refer, when avail-
able, DO less than 3 qualified applicants to
the chief pharmacist for interview, discussion
of the work and final selection In referring
these applicants, it should be the responsi-
bility of the personnel office of the hospital
to make whatever pertinent recommendations
may be indicated to guide the pharmacist in
making his selection The chief pharmacist
makes the final selection based on such fac-
tors as ability of the candidate to work with
the present personnel and his degree of effi-
ciency This IS usually standard procedure
for interviewing of hospital pharmacy per-
sonnel Obviously, proof of licensure should
be demanded Further, references concern-
ing the professional and moral character of
the applicant should be made only of mdi-
viduals who have current knowledge of the
subject
A rule-of-thumb approach to staffing needs
IS presented m Table 95, p 485
Use OF Nonprofessional Personnel
Nonprofcssional personnel (pharma^
helpers ) should be utilized wherever possible,
but never m activities requumg the skills or
the knowledge of a pharmacist Many activ-
ities, such as the collection and the delivery
of nursmg station pharmacy baskets, stock
checking, storeroom arrangements, perpetual-
inventory record keeping, dusting and clean-
ing, and prepackaging (under duect and
immediate supervision) may be allocated
properly to helpers Floor collection and de-
livery of baskets should be on a definite
schedule Most hospitals find, on experimen-
tation, that Monday, Wednesday and Fnday
“basket da)^” ser\c the hospital adequately
and allow the remainmg da)‘s of the week for
bulk-compounding prcpickaging and other
pharmaceutical or administrative activities
PHYSICAL FACILITIES
Faclliti» Adequate pharmaceutical and ad
nunistrative facilities shall be provided for the
pharmacy department, including especially
(A) the necessary equipment for the compound
jng, dispeosmg and manufacturing of pharma
ceulicals and parenteral preparations, (B) book-
keeping supplies and related materials and
equipment necessary for the proper administra-
tion of the department, (C) an adequate library
and filing equipment to make information con
ceming drugs readily available to both phar-
macists and physicians, (D) special locked stor-
age space to meet the legal requirements for
storage of narcotics, alcohol and other pre-
senbed drugs, (E) a refngerator for the storage
of Ihermolabile products, (F) adequate floor
space for all pharmacy operations and the stor
age of pharmaceutic^s at a satisfactory loca
uon provided with proper lighting and ventila-
tion •
The Complete Department
The current concept of a complete hos-
pital pharmacy department consists of the
following areas (1) a waiting area, (2) an
office for the CHiief of Service, (3) the out-
patient dispensing unit, (4) the manufactur-
ing or bulk<ompoundtDg mut, (5) the
stenle preparations unit, (6) the “m house,"
ward basket and prepackaging units, (7) the
pharmacy storeroom, (8) the research,
analysis and control umt, (9) the special
technics area, (10) the alcohol and volatile
liquid area, (11) the narcotic vaults, (12)
the allergy preparation unit, (13) a radio-
active isotope dispensmg unit, (14) the cen-
tral stenle supply area and (15) a "cold’
storage room with a regulated temperature
range of 12* C to 15® C. Items 1, 2, 5, 8,
12, 13, 14 and IS depend on the size of the
institution and the need and the desirability
for mclusion
Space Requirements and Layout
When one considers the progress made m
patient care since 1945 and the facilities
needed to give this modem care, one recog-
nizes the dur need for expansion space for
many of the old-lme hospital departments
Until recently, pharmacies, by and large,
vtcic "drug or dispensing rooms,” located in
•From “Minimum Standard for Pharmacies in
Hospitals “ with etude to application, as amended
November 8, 1962
Physical Facilities 487
the basement or some other out-of the way
place m the hospital Today, because of its
many and varied activities, the department
IS considered a “service,” not unlike the out-
patient, the dietetic, the radiology or the
nursmg service The phannaqr may have
several subdepartmenis such as outpatient,
pharmacy proper for house issues, manufac-
turmg, prepackagmg, bulk pharmacy storage,
drug-secunty vault, research, control and
analysis area, parenteral and surgical fluid
area, speaal techmcs area, allergy depart-
ment, and, more and more of late, central
sterile supply and, in some instances, a radio-
isotope prescnplion dispensmg umt These
subdepartments all demand certain mintmtim
square footage for their proper funcuonmg
Furthermore, where patients present them-
selves to the pharmacy for prescriptions, the
department nwist be no less presentable than
other patient areas, and must be located func-
tionally Today, hospital administrators favor
the concept that a phannaceutical service
should be located in a central place on the
first floor, adjacent to outpatient activities
and elevator facilities — m other words,
located functionally in relationship to ' trafiBc
flows ”
In plaomng a pharmacy or m remodelmg
one, it IS necessaiy to have some yardsticks
of measuremcut as to what is optimum and
reasonable space needs Fortunately, hospital
pharma^ has several such yardsticks
The old “Minimum Standard for Phar-
macies m Hospitals” {Bulletin of the Ameri-
can Society of Hospital Pharmacists, 5 232,
No 5) states that
Floor space in the pharmacy shall amount to
not less than five square feet per hospital bed
The hospital pharmacy engaged in the manufac
ture of pharmaceuticals and parenteral solutions
shall have additional space as required for the
proper carrying out of these functions
Table 96 Area Distribution for
General Hospital Pharmaoes*
Areas in
Square Feet^ SO-Bep 100-Bep 100 Be.p
Compounding and dis
pensing laboratory 205
320
495
Parenteral solution
laboratory
185
200
Active store room
125
200
Manufactunng
laboratory
Office and library
Circulation
120
105
60
Totals 205
630
1,180
• Hospital Faciluies U S Public Health Service
1953
t Areas shown are net areas and do not include
walls aod partitions Additional storage space is pro-
vided for bulk pharmacy stores in an area directly
beneath the pharmacy and separate from central
stores
Other authonties require 600 square feet
for the first 100 beds, 500 square feet for each
100 beds thereafter,* 1,000 square feet for
the first 100 beds, 500 square feet for each
100 additional beds.f each pharmacist
should have a working area of 20 square feet
counter space, 40 square feet floor space %
See Table 96 for U S P H S Standards re-
leased m 1951 (Pharmacy Department
Planning and Equipment for 50 , 100 , and
200-bed general hospitals Fourth Prmtmg
1961, U S Department of Health, Educauon
and Welfare, U S Public Health Service)
Hggres 171 and 172 illustrate specific
plans for pharmacies of 50 , 100- and 200
bed hospitals, keyed as to major equipment
needs
The floor space requirements presented by
•Momson in Hospitals 21 58 April 1947
tLatfve in Hospitals 20 63 March 1946
X Series E R. American Hospital Association,
aevcland 1944
Minimum Area (m sq ft.) Recommended by Guild Research and Plannino Committee for
A Pharmaceutical Department in a Completely Self swportino General Hospital
Beds
Dispensary
Sterile
Products
Dept
Prep Room
Stores
Office
Total
Beds
Ratio
Sq Ft
100
350
100
450
100
1 000
1 0-0
300
500
400
400
1000
150
2.450
700
800
550
500 to 650
2 400
200
5 000*
71
* Includes accommodation for stall antemues not shown separately
/fmr ran itw rf) «/ Ifoipi al Pharmaritlt
no 17! Pharmacy for a 50-bcd and a 100-bed general hospital (UJSPHS)
iicff far a JOO'hitl f/enwrtit hnmpitttl
490 Hojpitol Phormocy
Laws ond Regulohons 491
phannacy Attention is called also to the
need for explosion proof electric switches
and bght fixtures m the alcohol and the
volatfle hquids storage area, 220 volt electric
lines for heavy-duty equipment such as
mixers, the need of mcludmg, m biological
refrigerator specifications, automatic de
froster equipment, biological drawer inserts
and a freezmg compartment, the latter for
the storage of nonlyophilized smallpox and
yellow fever vaccmes, and the wisdom of
providmg sterilizers at least 24 m x 36 m x
48 m m size to allow for 2 level loads to
save labor cost on sterilizmg runs In this
connection, recent surveys* mdicate that 3 to
5 liters of salme and sterile water are needed
for each operation, with the average 200 bed
hospital consummg 122 hters daily Hot- and
cold water pipes m bulk-compounding areas
should be installed with water hose bibbs,
stills should be easy to clean and be installed
as complete umts with one or two 12 gallon
Pyrex storage carboys and a recordmg punty
meter
Four Items of equipment of special inter
est to the hospital pharmacist are (1) the
hand'Operated crimper for aluminum seals,
used especially in the preparation of stenie
solutions (Fig 174), (2) a tablet- and
capsule-countmg machine designed for hos-
pital-pharmacy prepackaging use (Fig 175),
(3) a hand-operated labelmg mac^e for
prepackagmg use (Fig 176), and (4) a
hand filler for fillmg bottles, jars, tubes and
other contamers (Fig 177)
Safety EQUiPAfEwr
Inequippmg the pharma^, attention should
be given to the installation of proper safety
equipment Fire extinguishers (carbon tetra
chlonde extmguishers must not be installed
for use m confined areas), fire blankets, fire
sprmklers and fire showers are important for
the safety of personnel and plant Some hos-
pitals insist that personnel operating steiil
izers wear shatter proof gog^es and head
gear and wire meshed asbestos gloves when
stenliziag hquids la glass containers, thus
mminuzmg accidents m cases of explosion
and glass^hattermg
• Schafer, M K. Sierthzers for General Hos
pltab (50 100 200 beds) Dmsioc of Medical and
Hospit^ Resources UlS Public Health Service
LAWS AND REGULATIONS
Space does not permit a discussion of the
laws and the codes apphcable to hospitals
and hospital phannacy The hospital phar-
macist should be familiar with Federal, state
and local laws as well as the common law as
they apply to the chantable trust doctrmc-
present legal trend, the hiring of hospital
pharmacists, the degree of skill and care re-
quired of the hospital pharmacist, the state
hospital licensing acts and regulations, the
legal aspects of PJLN orders, the liability
of the hospital for acts of the pharmacist, the
law concemmg the compounding and the
manufactunng of pharmaceuheal prepara-
tions covered by patent rights, prescriptions
as pnvileged communications, the statute of
limitation on suits for negligence, the laws on
substitution and duplication, the fire and
safety codes and regulations, the fair trade
laws, the Federal (Rustic Poison Act, the
Federal Insecticide Act, the Federal Food
and Drug Laws, the Therapeutics Trials
Committee (the Research Committee of the
Council on Pharmacy and Chemistry) of the
American Medical Association guide lines
on procedures for the clinical testing of in-
vestigational drugs, Federal laws and regula-
tions relative to industrial alcohol, tax-free
and tax paid (Regulation No 3), registration
of stills, the Federal Harrison Narcotic Act
( Regulation No S ) , and state and local phar-
macy and hospital laws and regulations The
hospital-pharmacy aspects of these laws arc
to be found m hospital and pharmaceutical
junsprudcncc texts (see Bibliography) and
Journals This chapter discusses the high-
lights of the major Federal laws
Narcotic and Other Records
IN Hospitals
One of the more important legal respon-
sibilities of the hospital pbannacist is that
of supervision and control of narcotics, hyp^
nolics, ethyl alcohol and sptnluoits liquors
Laws and Regulations 493
Fio 178
m the hospital Several systems have beco mmistratjon to the patient or the release of
developed to provide sound mtemal chechs the drug to an outpatient
on these items The system m use m the hos> One should note m particular that this type
pitals of the U S Public Health Service of control system provides “checks” hospit^-
throughout the country is presented (m form wise as well as pharmacy^wise This is essen-
manoer) as one method of handlmg this tial in hospital narcotic control The chief
activity. The 8 forms are numbered to show pharmacist who does not protect his hospital
the flow of the controlled drug from the time by assuming responsibility for this item from
of arrival at the hospital to their actual ad- the time of its arrival at the hospital to the
Flo 179
494 Ho]p tol Pharmacy
nnstwm i~i »i n.r*
a^ia*"" ••
Fia 180 (U^PII^)
time of consumption or release to the patient
15 not fulfilling his duty m this area It is of
special importance that security controls be
in operation that check transfers of supplies
from the pharma^ through the nursing
medication stations In the system illustrated,
the pharmacist prepares these audits monthly
and ascertains the status of all outstanding
cectiBcatcs of disposition (Fig 181. Form
1435-2, No 4)
Harrisov Narcotic Act
Registration Hospitals are registered m
class 4 (authority to administer narcotics),
classes 4 and 5 (class 5 gives authority to
deal m “exempt" narcotics), or classes 3, 4
and 5 (class 3 is for retail dealers and is used
for hospitals dispensing narcotic presenp-
tions to outpatients) Physicians attached to
a hospital may not use the narcotic registra-
tion number of the hospital, the so-called
narcotic number, to write prescriptions or
orders for an individual patient
Practitioners who presenbe narcotics for,
or order narcotics dispensed to, patients m a
Flo. 18! )
Laws and Regulations 495
hospital must be entitled under the laws of
the state, the temtory or the distnct (Medical
Practice Act) to prescribe or order dispensed
narcotic drugs and must be registered with
the Director of Internal Revenue for this
purpose
Interns, residents and medical officers who
are attending patients m hospitals, if entitled
under the State, Territorial or Distnct Medi-
cal Practice Act to prescnbe or dispense nar
cotic drugs to patients in the hospital, may
obtam the requisite registration from the
Treasury Department, Director of Internal
Revenue, to complete their qualifications to
write prescnptions for, or order narcotics dis-
pensed to, hospitel patients m the course of
their professional practice However, this
authonty is limited to the patients assigned
to the mtem, resident or medical officer, and
no others
Usually, the State, Temtonal or Distnct
Medical Practice Act sets forth the require-
ments for the professional right to prescnbe
and dispense narcotic drugs The licensed
physician, dentist or vetennanan m good
standing has this nght However, there may
be a question as to whether an intern or a
resident has such a nght, even as limited to
hospital patients, unless the Medical Prac-
tice Act or other statute confers this author-
ity If It IS determined aulhontatively that the
mtem has such a legal right limited to hos-
pital patients, he may apply for a registration
under the Federal Narcotic Act This is a
matter which must be determined m each
state Some authonties on this subject beheve
that the laws of most states do not authorize
the mtem to prescnbe for, or dispense nar-
cotic drugs to, a patient on his own inde-
pendent professional judgment In such m
stances, Uie mtem cannot be authorized to
prescnbe narcotics by the Bureau of Nar-
cotics because the mtem is an unlicensed
practitioner In the former mstance, qualified
or restncted licensmg gives the authonty
The administrative head of the hospital as
a registrant is responsible for the proper safe-
guarding and handling of narcotics withm
the hospital Responsibility for storage, ac-
countability and proper dispensmg of nar-
cotics from the pbannacy usually is delegated
to the pharmacist Likewise the director of
nursmg usually is responsible for the proper
storage at nursmg stations and use as di-
rected by physician orders However, delcga
Uon of authonty does not relieve the admin-
istrative head of the hospital of supervisory
responsibility to ensure detecuon and correc-
tion of any diversion or mishandlmg The
administrator should be certam that all possi-
ble mtemal control measures are observed
A doctor’s narcotic orders for patients
nonnally appear on the doctor’s order sheets,
no prescription is required The nursmg floor
Fio 182 (U^PJIS)
496 Hospifal Phormacy
stock used in adnumstcrmg narcotics is ac-
counted for on the narcotic Certificate of
DisposiUon
The doctor’s full name or mitials must ap-
ar on the doctor’s sheet His registry nura-
T IS not needed
Telephone orders are permissible only in
absolute necessity The nurse will write the
order on the doctor’s order sheet, staling
“Telephone Order,” and sign the doctor’s
name and her own iniuals The narcotic may
be administered owe The doctor must \enfy
on the patient’s chart withm 24 hours
Verbal orders are permitted in a bona fide
emergency They should be handled as tele-
phone narcotic orders
Procedure In case of waste, destruction
and contamination:
1 Aliquot Part of Narcotic Solu-
tions Used for Dose The nurse should use
the proper number of tablets or ampuls from
the nursing unit stock She should expel mto
the sulk that portion of the narcotic solution
that is not to be used She should record the
number of tablets or ampuls used and the
dose given in the proper columns on the Nar-
^ s! ( 3 )
Te Mniiul 0(ftc«r iB curn
Itnudi ClUlal Dicectsr
Suajtei Karcotlc Audit R«p>rt
I rrmrt ,fi,t m m luAlf nf nirmHf InvMfBrlfi »•« uriB
Md the iBTraietKi scUait tte lirr^tal InrrDiBrr rteoru nis Audit Incladcd
1 A ewet «r (!• AMKtlrUaM u* rtutiilduM w t« MttHIUld ul Mrrict peittip
I A ci«et M l< tH KCutKI IM fMIUI AltuURtl Ml
1 A* MtHl <nai tl ilptcAl (tKU Md MCMciilAtM «lit Ut pUntcj MtCMie Tteerl,
foUoilfli dlictipABcln terf octfd (if mm vrii* mm)
IT 11 rtcaiMiUrd tbit • luiri)' te
et f/faoM >rl(« mm)
Mf to deura
U* tte rttsan
f9r tte in«TCotl]r eiceisite met
no.
•"* M 'BHO-T
•
J
Fio 184 (U^PH5)
Laws and Regulations 497
Fio 185 (U^PH^)
498 Hojpife! Phormocy
cotic Administration Sheet (the Certificate
of Disposition)
2 Prepared Dose Refused BY Patient
OR Canceled by Doctor When a narcotic
dose has been prepared for a patient but not
used due to refusal by the patient or cancella-
tion by the doctor, the nurse should expel
the solution into the smk and record on the
back of the Narcotic Administration Sheet
the reason sshy the narcotic was not admin-
istered {Example “Discarded Refused by
patient or order canceled by Dr A Jones “)
The head nurse of the unit should sign the
statement and the director of nursmg or her
assistant countersign it
3 Accidental Destruction of Nar-
cotics When a narcotic solution, tablet,
ampul or substance is destroyed accidentally
on a Nursmg Umt, the person responsible
should indicate the accidental loss by a check
in the spaces allosiicd for the record on the
Narcotic Administration Sheet of that nar-
cotic The person should write on the back
of that Narcotic Administration Sheet a com
plcte report of the accident and sign the state-
ment The head nurse of the unit should sign
the statement sshen complete Then the &•
rector of nursmg or her assistant should sign
the statement also
4 Contaminated or Broken Hypo-
dermic Tablets and Contaminated Nar-
cotic Solutions When a narcotic hypo-
dermic tablet is contaminated or broken or
a narcotic solution is contaminated, the per-
son responsible, or the head nurse, should
place the tablets, the particles or the solution
In a suitable contamcr and label them The
person responsible, or the head nurse, should
indicate the contaminated narcotic by a
check in the space or spaces allowed for the
record on the Narcotic Admmistration Sheet
of that narcotic She should wntc on the back
of the sheet a complete report of the accident
and sign the statement. The head nurse
should sign the statement when complete
The director of nursing or her assistant
should then sign the statement The container
with the contaminated narcotic should be re-
turned to the pharmacy The pharmacist will
reccn’c it and note on the Narcotic Admin-
istration Sheet cownng that particular nar-
cotic that It has been rctumeiL The hospital
should return the matenal either by itself or
with similar narcotic material at a convenient
time to the Narcotic Bureau in the proper
manner
In using the above procedures, the head
nurse shodd sign entnes as a witness In ad-
dition, a professionally responsible super-
\TSory official should mitial the entnes to
assure an awareness on the part of super-
visory professional personnel of all matters
relating to narcotics
Procedure in case of loss and (heft:
1 Discrepancies m narcotics count m-
volving small amounts (such as single doses)
should be reported to a responsible super-
visory official An mvestigation should be
made to determme the cause of the loss A
copy of the report of investigation, signed by
the responsible supervisory official, should
be filed with the hospital narcotic records
and appropnate action taken to prevent re-
currence
2 In cases of recurring shortages, or
LOSS OF significant quantities of narcotics
(several doses), a thorough investigation
^ould be made, makmg every efiort to de-
termine the reason for the shortage and the
person responsible, if possible, with a com-
plete report of the incident and findings made
to the administrative autbori^ of the hos-
pital Appropnate action should be taken
immediately to prevent recurrence A copy
of the report, mcludmg any findings resull-
mg from the local investigation, should be
forwarded to the District Supervisor of the
Bureau of Narcotics, in accordance with
Article 194, Bureau of Narcotics Regulation
No 5
Questions concenung Interpretation of the
law and regulations as they apply to hospitals
should be duected to the Commissioner of
Narcotics m Washington, D C
Questions on taw and regulations viola-
(Jons should be directed to the local narcotic
a^nts
Hospitals arc registrants m class 4 (to ad-
iiunister narcotics) if without outpatient de-
partments, m classes 3 and 4 if they operate
an outpatient department This is one of the
annoying problems in hospital pharmacy and
hospital administration Separate slocks and
separate imentory records must be roain-
tamedfor each class (classes 3 and 4) Class
3 applies to retail dealers m narcotics, and
Laws and Regulations 499
It has been ruled that hospitals and clinics
must register m this class »/ prescriptions are
dispensed to outpatients by the hospital
pharmacy Class 4 applies to physicians and
other practitioners who administer narcotics
to patients This is the registration dass re-
quired for hospitals with inpatients
The MuUiple-Dose Vial Problem. It is
claimed that nurses seldom obtain the theo
retically possible number of doses from a
multiple-dose vial The Bureau of Narcotics
has suggested that hospitals use the VS P
and N F limit of tolerances as a guidepost
— 1 e , 2 to 20 per cent dependmg on the size
of the vial
‘ Standmg ’ and ‘ P R N ” orders for nar
cotics are permissible, but they should not
be given for periods exceeding 72 hours, re
gardless of the type oj case — terminal, cancer
or otherwise This helps to elumoate the
chances of drugs bemg diverted illicitly after
the death of a patient
Storage. Narcotics must be kept m a
locked, secure place Reserve stocks should
be kept m a * strong safe substantial enough
to deter entry and heavy enough to prevent
their bemg carried away ” Other valuable
property may be kept m the safe A chest or
safe meetmg Underwriters Laboratories re-
quirements for an X 60 tatuig is designed
to offer protection against attack by tools or
cxplosues for a period of 1 hour, one with
a TR 60 rating protects against tools or
torch, one with a TX-60 laUng protects
against tools, torch or explosives for the
same period of time A safe with any of
these ratmgs, or of equivalent construcboo,
IS considered a ' strong safe by the Bureau
For small stocks, the Bureau of Narcotics
has occasionally, though reluctantly, accepted
lighter safes with only a T-20 ratmg This
type of safe is built to resist attack by ordi
nary burglar’s took only, and only for a
period of 20 minutes While better than no
safe at all, it offers a bare mmimum of pro-
tection Although sometimes msisted on as
a minimum requirement, it is never recom-
mended as adequate and certainly is not ade-
quate for safekeeping of a narcotic stock of
any appreciable size or value
Any safe weighmg less than 750 pounds
should be securely anchored m concrete to
the floor or the wall to prevent its bemg ear-
ned away If bolts are used, they should be
imbedded completely so that they cannot
readily be reached and cut, sawed or un-
bolted (see General Cucular 195, Bureau of
Narcotics)
The president of the hospital corporation
is usually the mdividual m whose name the
narcotic registration is issued However, he
may delegate certam authonty to proper em
ployees of the hospital, for example, he may
delegate to the registered pharmacist author-
ity to sign forms He may not delegate the
right to sign the application for registration
Applications of corporations must be signed
by an officer duly authorized to act (Article
8 of Regulation 5) Supposedly, this refers
to the president, the vice president or the
secretaiy
The hospital hcense must be renewed
annually on or before July first
A physician cannot replenish his office
narcotic supply or his physician’s bag sup-
plies from the hospital pharmacy narcotic
supplies He must order from a drug whole-
saler on a special narcotic order fonn An
exception rarely, if ever, used is the single
ounce of an aqueous or oleagmous solution
of not over 20 per cent when ordered on the
physician s official Federal narcotic order
blank, not on his prescription blank (Article
XVoftbeAct)
Though not discussed here, the regulations
that apply to the bandlmg of narcotics m
commumty pharmacies apply also to hos-
pital pharmacy
Closes of Narcotics. General Circular No
262 classifies narcotics into four categones
Class A — fully controlled narcotics that
requuc a written signed prescnption
Qass B — ^narcotic drugs authorized for
oral prescription
Class X — exempted preparations which
may be sold without a prescription
Qass M — specially exempted preparations
which may be sold without a prescription
It is of special mterest to hospital pharmacists
to note that Qass M narcotics are exempt
from record keeping at the hospital Ex-
amples of Qass M drugs are Papaverine and
Nalorphine (Nallme) preparations It is only
the original sale by ffie manufacturer that
need be recorded for Qass M preparations
500 Hospifol Pharmacy
Federal Food avd Drug Code and
Regulations
Pmcnptions for prcscnption legend drugs
ma) not be refilled unless authorized by the
physician or the dentist
Prescriptions for prcscnption legend drugs
must contain on the label ( 1 ) the name of
the prcscribcr, (2) the serial number and
the date of filling, (3) the name of the pa-
tient, if on the prescription, (4) any direc-
tions or warnings given in the prcscnption
(signa) and (5) the name and the address
of the store or the hospital
Oral prcscnptions from phj’sicians and
dentists for such items should be noted in
wnting by the pharmacist and filed The
pharmacist must record ( 1 ) the date and the
serial number, (2) the names of the doctor
and the patient, (3) the items and the quan-
tities prescribed, (4) directions and cautions,
if any and (5) refill directions, if any
The doctor’s oral refill authonzation
should be noted on the original prescription
While the Act may not specifically require
the exact procedure as indicated m this and
the preceding paragraph, the adoption of
such procedures meets m full the require-
ments of the law
The Statute of Limitations for violations
of the Dutham-Humphrey Act is 5 years
During this period prescriptions, medication
orders and purchase orders should be kept
as evidence of compliance with the Act
(1954 Amendment, USCA Title 18,
Crimes and Criminal Procedure, 1959
Annual Pocket Pact for use during 1960,
Title 18, Chapter 231 Limitations, Section
3282, Offenses not Capital, The Prescrip-
tion Legend, a FDA Manual for Pharma-
cists, p 12)
Federal Code and Regulations
Pertaining to Ethyl Alcohol
Nonprofit hospitals and clinics may obtam
tax-free alcohol for use In the hospital or
the clinic, including use in the compounding
of bona fide medicines for treatment of clinic
patients outside the chmc, but such medicines
may not be sold (Section 3108 (C) of the
Internal Revenue Code of 1939 and Section
5310 (C) of the Internal Revenue Code of
1954).
Hospitals operating outpatient depart-
ments and charging for prescriptions contain-
mg alcohol (such as phcnobaibital elixir,
tcqjin hydrate elixir, terpin hydrate elixir
with codeine and belladonna tincture), dis-
pensed to outpatients may not use tax-free
alcohol in these preparations
Tax-free alcohol may not be used m the
preparation of condiments, culinary extracts,
flavoring or other preparations used m food
products This exception specifically pro-
hibits the use of tax-free alcohol m the mak-
ing of vanilla, lemon, maple or other flavor-
ing extracts by the pharmacy for the dietetic
service of the hospital
Federal Code and Regulations
Pertaining to Stills
Stills must be registered with the Assistant
Regional Commissioner, Alcohol and Tax
Division of the Region (Regulation 23, In-
ternal Revenue Service)
This regulation applies only to stills used
or intended to be used for the distillation,
the redistillation or the recovery of distilled
spmts, mcludmg alcohol or any dilution or
mixture thereof (Section 5174, Internal
Revenue Cede) Prior to the Internal Rev-
enue Code of 1954, stills used for distiUmg
water or the preparation of drugs or chem-
icals or for recovering cleanmg fluids were
required to be registered This is no longer
a requirement
INVESTIGATIONAL DRUGS
Statement of Principles
Involved in the Use op
INVESTIOATTONAL DRUGS IN HOSPITALS*
Hospitals arc the pnmary centers for clinical
investigations on new drugs Dy definition these
are drugs which have not yet been released by
the Federal Food and Drug Administration for
general use
Since investigational drugs have not been certi-
fied as being for general use and have not been
cleared for sale in interstate commerce by the
Federal Food and Drug Administration, hos-
pitals and their medical stafls have an obliga-
• Developed by the Amencan Ifospital Associa
lion and the Amencan Society of Hospital Phanna
cuts Joint Committee
Safety Practices 501
tion to their patients to see that proper pro-
cedures for their use are established
Procedures for the control of investigational
drugs should be based upon the following pnn
ciples
1 Investigational drugs should be used only
under the direct supervision of the pnncipal in
vestigator who should be a member of the medi
cal staff and who should assume the burden of
securing the necessary consent
2 The hospital should do all in its power to
foster research consistent with adequate safe
guard for the patient
3 When nurses are called upon to administer
investigational drugs, they should have available
to them basic information concermng such
drugs — including dosage forms, strengths avail
able, actions and uses side effects, and
toms of toxicity, etc
4 The hospital should establish, preferably
through the pharmacy and therapeutics com
mittee, a central unit where essential laforma
tion on investigational drugs is maintained and
whence it may be made available to authorued
personnel
5 The pharmacy department is the appro-
priate area for the storage of investigational
drugs, as it is for all other drugs This will also
provide for the proper labeling and dispensing
m accord with the investigator’s written orders
It will be noted that the statement ensures
that the hospital, its nurses and pharmacists,
as well as the physicians evaluatmg an in-
vestigational drug m clinical practice, will
have complete information available to them
within the institution In this connection, the
code to break, the “double blind and other
studies IS available m the event of an adverse
or unexpected reaction from the admmistra
tion of an mvestigational drug to a patient
Theoretically, similar information is readily
available m * remote coding ’ programs by
telephoning the central point and breaking
the code there, however, communication diffi-
culties may result m dangerous delays
SAFETY PRACTICES
Keep narcotics, hypnotics, amphetamines
and poisons stored separately m locked
cabmets
Keep narcotics m as small supply as is
expedient
Keep TOlatile liquids m a cool place
Store acids and other irritating liquids
below knee level
Verify the accuracy of pharmaceutical cal-
culations with a mental estimate of the
answer
Where possible, have a second person
check the pharmaceutical calculations on
preparations requirmg weights and measures
^eck each prescription with a second
pharmacist, if possible
Check labels 3 tunes first as the item is
taken from the shelf, secondly when used
and lastly when returned to the shelf
Verify the accuracy of the label by careful
qiacToscopic exammation of the material m
the contamer
Use every precaution to prevent a pre-
scription label or a stock-container label
switch
Permit no unidentified substance to remam
m the pharmacy
Pour below eye level and avoid splashmg,
handle strong chemicals with care
Give close attention to matenals being
heated Do not leave process unattended
Be certain that you have fulfilled the in
tent of the presenber before dispensing the
prescription
Use the check system to ensure delivery of
the proper prescription to the patient
Include ffie patient s full name on the label
pf each prescription
Use strip labels” when indicated, such as
• eyedrops,” ‘nosedrops,’ “Do not use after
• ,”ctc
Make certain that the patient fully under-
stands how to take the medication
Where the presenpuon calls for a phar-
jnaccutJcal specialty, a basic drug or bio-
logical, place the name of the manufacturer,
the trade name of the product (if any) and
the manufacturer’s lot control number on the
reverse side or face of the prescription (See
fig 180 )
Use dual code labels m prepackagmg
fxave one label on the container, afiSx the
Other to the prescription bemg filed.
Also, the use of a code number on all pre-
packaged and floor stock contamers which
identifies the entry of that item m the chron
ological log IS highly desirable to ensure
ijuolity control For example. Code No
Fjo 186 (Top) PharmaccuticaJ formulation control record (Doliom) Rcvcnc side
(U^PH^)
1163105 indicates that the item was pro- ot the pharmacist responsible for the pack-
packaged in November 1963 and was the aging. <2) the name of the manufacturer
105th Item packaged With this information, and (3) the manufacturer’s lot or control
It IS possible to find in the log (1) the name number
Volume Compounding 503
Fig 187 (USPHS)
VOLIJME COMPOUNDING
Volume compounding or bulk compound-
ing are relatively new terms applied by hos-
pital pharmacists to the manufacturing of
phannaceuticals in hospitals
When to manufacture is often a difficult
problem to decide A simple lule-cf-thumb
used by many pharmacists is to manufacture
only those items that may be prepared m as
good or better quality at a cost less than or
equal to the purchased item Obviously, items
not commercially available must be manu-
factured
The problem of when to bulk compound
becomes more complex where the hospital is
a teaching one Here, the hospital has teach-
ing obligations as well as patient care respon-
sibilities, and, while a high-quality medication
standard must be adhered to, an increased
cost can be justified for bulk compounding on
the grounds that it is necessary for the intern
to become familiar with manufacturmg tech-
nics and with the operation of equipment
such as blenders, filter pumps, homogenizers,
ointment mills, tanks, mixers, bacterial filters,
stenilzers, prepackaging and labeling equip-
ment and similar items
An important factor m bulk compoundmg
over and above formulation, research and
actual compoundmg problems (subjects dis-
cussed m other chapters) is that of controls
Reproduced below in Figures 186 and
187 are 2 forms used in the Public Health
Fia 188 Bulk compounding unit in a hospiul pharmacy (USPHS Hospital, Seattle)
Service Hospitals bulk-compounding activ
Hies These arc self-explanatory of the sys-
tem involved It will be noted that the manu
facturing worksheet (Fig 187) carries not
only the name of the drug or the chemical but
also Its source and the manufacturer’s or sup-
plier’s package control number
Many items in the hospital pharmacy ob-
xiously lend themselves to bulk compound
mg at considerable savings to the institution
PREPACKAGING
The larger hospital pharmacies with heavy
nuising-station medication orders (basket
filling duties) and outpatient prescnption
activities fmd it good management practice
to prepackage the heavy repeating items
Prepackaging consists of packaging in dis-
peming-size units large quantities of fast-
moving Items m advance of actual need The
tune saved is considerable masmuch as the
pharmacist merely replaces the empty con-
tainer returned from the floors with filled ones
or need concern himself only with individual
outpatient prescription labeling for the pre-
packaged prescnption item The prepackag-
ing process places the preparation of these
Items at ofl-^ak penods This type of oper-
ation ensures neat, clean containers with
property shellacked or varnished labels, mov
ing to the floors at all times, as well as an
adequate prepackaged stock of individual
paticnt-size prescription items
Obviously, a control system must be ap-
plied also to prepackaging because of the
shelf life of the items A self-explanatory 2-
fonn control system is illustrated in Figures
190 and I9I
Fig 190 (USPHS)
506 Hotpifal Pharmacy
Labels and Containers 507
STANDARDIZATION OF
PRESCRIPTION AND WARD ISSUE
MEDICATION CONTAINERS
While It IS realized that medications for
ward, clinic and outpatient use are consumed
normally m relatively short periods of time
after being dispensed from the pharmacy, it
IS known also that many such medications
have long “shelf hfe ” Adequate protection
should be provided to maintam the full ther-
apeutic effectiveness of these preparations
It IS for this reason that many hospital phar
macists standardize their prepackaged ward,
dime and prescnption containers to the
amber-type contamers used by manufacturers
m complying with VS P and N F require-
ments to “store and preserve in tight light-
resistant contamers ”
INPATIENT DISPENSING
Two Unit Container System
Prepackaging m the larger hospital phar-
macy as an important element of the m-
patient dispensmg activity has been discussed
In the smaller hospital, prepackaging may not
be either desirable or practicable Many small
hospitals prefer what may be termed the Dual-
Container Ward and Qmic Issue System
This system operates as follows
1 All items having quantity usage are
kepi at the nursing station medication center
in 2 identical standard-sized containers (the
size varies with the size and the number of
tablets or capsules or the volume of Ucpiid re-
quired for a mmimum supply for 1 or 2
weeks
2 The label on each container shows in
the upper left hand comer the home station
of the contamer such as ‘4 East”, m the
upper right hand comet (or as a separate
‘ strip” label) is the control number described
previously under “safety practices”, m the
center of the label appear the name of the
drug or preparation and directly underneath
the unit strength (metnc), the approzunatc
capacity of the container m miUililcrs or
units IS typed m the lower nght hand comer
3 The charge nurse or her assistant
checks medication needs prior to 9 00 a m
on “issue days ”
4 Any contamer that is empty or no
longer needed is placed m the drug basket
for return to the pharmacy
5 The 2-UDit Contamer System provides
for a full contamer remammg on the floor
whde an empty contamer is bemg refilled
This elimmales the dangerous practice of
placmg the few remaining tablets or milli-
liters of a liquid m a medicme glass to satisfy
ward needs while the sole contamer is at the
pharmacy for refiUmg
6 The charge nurse prepares the requisi-
tion m the usual fashion by fiUmg out a phar-
macy requisition form m dupheate
LABELS AND CONTAINERS
Neat, well-designed labels are important to
the hospital and its pharmacy In the home
of the patient, as well as throughout the hos-
pital, they speak for the hospital Illustrations
of the 3 major type labels (prescription,
wammg strip and pharmai^) used m hos-
pital pharmacy are reprodaced as examples
of good label design m Figures 193 to 200
Prescnpfion Labels. Rolls of 500 Prmted
in blue tnk, with hospital location (size
inches by IVt inches)
Fio 193 (U^PH3)
Warning Sfnp Labels Rolls of 250
Prmted m red tnk (size U/4 mches by
mch)
508 Hospitol Pharmacy
Pharmacy Labek. These labels allow space
for Ihc Public Health Service station to in-
sert the station location by use of a rubber
stamp or by typing Labels arc packaged in
individual boxes of 100 labels
Printed in blue ink, (size 2 inches by 1
inch, rounded comers)
jVbf to be Swallovicd
Fro 194 (U5PHS)
Printed in blue ink (size 1V4 inches by
Vt inch)
Kf lOrtai tf luini texiTioa. ui ituai '
rXMK HtAlTH timCI
CHLORAMPHENICOL
CAPSULES
(CJifsr^mjrcellnl
OJS Om I
FOR EXmXAl SSE ONLY
NASAL MrOICATION
POR THI EAR
Fro 195
Printed in blue ink (size IW inches by
44 inch)
Printed in blue ink (size 1*4 inches by
mch)
iirtumiiTei luinun-uncii iMiuiiu'
rviuc HtMIM u«nci
0I6ITAUS
TAILETS
01 Sm IIM
Krtr mraisiRATco
f/’Ty. wuiK« » Bam iwiroi. u> min'
/«) fVfOC MUITM MITICI
nPrtttKNJMtN! imKNtOtlS!
TABLETS
(Rrrlbtiiiamlnil
10 my
Fro 197 (U^PFKS)
Fro 198 (U3PHS)
rnspedfon of Nursing Station Medication Units 509
Pnnted in blue ink (size 2^A inches by
1V4 inches, rounded corners)
Printed in red ink (size 2Vi inches by
VA inches, rounded comers)
BENZALKONIUM CHLORIDE
SOLUTION
wtlh Seep
PARALDEHYDE
Ifeep tightly C/eted
DiriilHiit Of lUim (lucitioi mg rufiit'
*VIUC HCAITH tunc*
ACETYLSALICYLIC ACID
TABLETS
MipMoJ
OJ Gm. (6 frolml
-
m
OirilTHKI Of IttlK. IISClI'OI HI VU'Ht
Miue KuirH siivicf
SULFISOXAZOLE
TABLETS
ICsnMsln)
0 5 Gm. <7V> groliitl
.
POTASSIUM IODIDE
SOLUTION
(SetvretcW F«letit«m Midt Sefirtteiil
1 Gm. (II qretii) per eiL
ujr owr WHIN coioiins
Fro 199 (U^PHS)
POISON
CAUMINC
LOTION
wall
PKEKOI.
SHAKE WELL
. fOK EXTEKNAL USE ONLY
Fio 200 (USPHS)
Labeling and renewal of containers for
ward and clinic medications is the responsi-
bility of pharmacy personnel No item should
be labeled by number or corned name, where
trade names are employed, the generic name
should be used also
Labels of all medications, other than those
of the individual patient prescriptions, should
be varnished or shellacked to mamtam pre-
sentable label longevity The use of adhesive
tape as labels for stock medications should
be discouraged All containers should be
checked routinely for appearance and un-
sightly containers and labels changed
promptly Labels and contamers should be
inspected as issued No label changing should
be done by other than trained pharmacy per-
sonnel
HOUSE REQUISITIONING OF DRUGS
The use of a prmtcd or mimeographed
pharmacy requisition form is desirable m the
handling of ‘ house orders ” A typical form
of this bnd is reproduced m Figure 201
INSPECTION OF NURSING-STATION
MEDICATION UNITS
The monthly inspection of each nursing-
station medication unit by the chief phar-
macist and the director of nursmg as part of
their supervisory duties (Fig 202) has been
discussed previously Outdated and surplus
stock IS kept to a minimum by this routine in-
spection Label and container condiuon is
detected quickly, also, violations of hospital
regulations relative to narcotics, hypnotics
and other controlled drugs are subject to ex-
posure by alert mspections
510 Hospital Phorraocy
ItWoo PHARMACY REQUISITION
rupsrc I" IT ciiABC itjrse sic* ^dats^
Th« nursing unit drugi listed b6'»o» «r« for comrorieneo in ordering. This
fore is to be used on raguler "issue dejs" only. Preserlptlon fom fo. 565 i* to
be used for en energmey itea es uauel*
Dosipieto cunbor of unite rented in the colirui directly to the left of the
Iten. Indlcete the unit quantity directly to the right of the Iten If not already
entered. Tfrite "new" after Itene requiring a new peraanent container, otherwise.
Item will net be dispensed. FR5PAE5 m PffUCATB AMP SSM) ROTH COPIES TO PHABMACT.
1
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‘TOTAh ISSIfES
rio 201 Pharmacy requmtion fonn (USPHS)
Emei^ency and Anlidotoi Drugs Cabinet 511
Fic 202 Inspection of a nursing sta*
tion medication unit by a director of
nursing and a chief of a pharmaceuti-
cal service (USPHS )
OUTPATIENT DEPARTMENT
The outpatient prcscnption service is an-
other vital activity performed by the hospital
pharmacist Inasmuch as many of the factors
to be considered here are the same as those
involved m the dispensing of prescriptions at
the community pharmacy, this topic will be
treated by mention of only those key points
to be observed in maintaining a well-operated
department
A prescnption check (Fig 203) should be
issued to each patient
Labels should be typed neatly and should
carry the prescnption number, the date, the
patient’s full name, the signa and the phy-
sician’s name as well as the name and the
PHARMACY DEPARTMENT
PleaM be seated iintO the phannaost calls
yonr name or the numbers listed below
eaescRiPTiON no .
NCW4.0C. KT
Fio 203 Prescription check (USPHS)
address of the hospital and the initials or
name o! the pharmacist (Some hospitals re-
quire that the prescription contents (medi-
cation ideotiUcatiOD and strength) also be
typed on the label unless presenber requests
otherwise )
Proper “strip” or ‘ supplementary" labels
should be used
The patient should be presented with a
neatly wrapped package
‘Counter prescribing," attempts to diag-
nose, discussion of prescriptions in a deroga-
tory manner with a patient, or discussion of
the disease or the ailment for which the
pharmacist believes the prescription is in-
tended, are, of course, prohibited by ethics
EMERGENCY AND ANTIDOTAL
DRUGS CABINET
Most hospital pharmacies maintain an
eme^ency cabmet stocked with ready to-usc
emergency and antidotal drugs and mforma-
tion on clinical toxicology TTiis is especially
important today with the increased number
of household and economic poison cases
entenng the hospital The contents of such
kits IS properly the responsibibty of the phar-
macy committee of the hospital Periodic m-
512 Hosptfol Pharmacy
Table 97. Typical List of Emeroescy
AVD Antidotal Drugs
Amphetamine sulfate 20 mg /ml ,
I ml
6
Atropine sulfate, HT, 04 mg
100
BAL in oil, lore, 4 5 ml
2
ColTcine sodium benzoate,
0.5 Cm /2 ml
3
Calcium gluconate lO'^-lO ml
6
Cornstarch
120 Gm
Cottonseed oil
240 ml
Epmephnne HCl 1 1,000
30 mt
Magnesium sulfate
120Gm
Milk of magnesia
240 ml
Mineral oil
30 ml
Nikethamide 25?o-5 ml (Cornmine)
2
Picroloxin 0 3$o
20 mi
Pentobarbital sodium injection
0 25 Gm , 5 ml Amp
2
Sodium bicarbonate
l20Gm
Sodium Chloride
!20Gm
Sodium lactate 1 Molar —
40 ml Amp
2
Universal antidote
t20Gm
Zinc sulfate
1 3Gm
I V Fluids kept in designated section of
Pharmacy
spcction and replenishment of these supplies
IS the duty of the pharmacist
Table 98 Zuctai System for Deter-
mining Drug Oiarces*
A hospital can use this equation as one basis
for reasonable, consistent drug charges Cost
fluctuations and diiTcrenccs in dollar value thus
may be adjusted and the pharmacist may main-
tain better control of his department, its surplus
earnings, its financial needs and its fairness to
hospitd and patient
Desired income
from drugs
Cost of prescription
drugs
per cent above
X 100 = cost to be charged
for prescriptions
1 Determine desired income from drugs
2 Divide desired income by cost of prcscrip
tion drugs
3 hfulliply the result by 1 00
In one hospital, where no profit from pre-
scription drugs was desired, the formula was
used in this manner
1 Desired income, based on cost of medica-
tions issued without charge to patients
Total nursing unit expense 3,153 06
Auxiliary professional unit
expense 280 83
Narcoucs 80 00
Nuisance prescriptions 215 38
Pharmacy salaries and other
expense 1,284 62
DRUG CHARGES
The hospital should have an approved uoi-
form schedule for the charging of drugs
There arc several systems m use They may
be classified as
1 The all-incIusivc or no-spccial-charge
rate The cost of medications is absorbed in
the all-iRclusivc day rate
2 A part-inclusive rate Charges are made
for medications not on the “free” or “sup-
plied ’list
3 A cost-plus rate (sec Zugich system in
Table 98)
4 A flat rate for each outpatient pre-
scnption
5 The suggested list or fair-trade price
6 Actual cost of medication plus a pro-
fessional fee (the preferred system and one
that IS growing m acceptance)
PURCHASING
Normally, drug supplies for hospitals arc
Desired income (tabulation) 5,013 89
Desired surplus earnings 00 00
Desired income to meet
expenses 5,013 89
2. Cost of prescription drugs $6,430 00
3 Above cost percentage
$5,013 89 (desired (per cent above
mcomc) „ ICO = -JB
$6,430 (prescnption charged for
cost) prescnptions)
The 78 per cent represents the mark up neces-
sary to meet all pharmacy costs and to place the
pharmacy on a self paying basis with no desired
profit
* rrom John Zugich Assistant Director, Uni
venity Hospital, Univenity of Michigan, Ann
Arbor
purchased m one of the following ways. (1)
by bid, (2) by direct order to the pharma-
ceutical or the chemical house or (3) from
the local wholesaler However, the subjects
Management Responsibilities 513
Fio. 204. Section of the central sterile supply service of tbe pbannaceutical service of the
Clinical Center of the National Institutes of Health. (U.S.P.H.S.)
of drug buying and pharmacy administration
— in general Uke subjects such as the manu-
facture of sterile and nonsterile preparations,
ophthalmic solutions, formulation studies,
pharmaceutical research and kindred tech-
nical problems common to the profession —
are not within the scope of this chapter.
Much of this material b to be found either
in this volume or in Sprowls’ American
Pharmacy.
CENTRAL STERILE SUPPLY
Some of the larger pharmacies operate as
subdepartments the central slerfle supply
service of the hospital. This department is
responsible for providing sterile items such as
dressings, syringes, needles, sterile solutions
(parenteral and surgical), trays and s imila r
items. The smooth functioning of this activity
is accomplished best by bringmg problems in
this area to the pharmacy committee and a
special procedure committee representing
nursing and pharmacy.
MANAGEMENT RESPONSIBILITIES
Good management on the part of a depart-
ment bead presupposes his ability to com-
bine the factors of men and money, time and
“tools” to produce an efBcient, economical
end product — in this instance, a good phar-
maceutical service.
No department head can expect to perform
this feat without the management tools of
responsibility and accountabUity. The tools
of management, other than men and money,
needed for sound hospital pharmacy admin-
istration are:
1. An inventory policy
A. Storage
B. Perpetual inventory records
2. A monthly or quarterly and an annual
reporting system of workloads and costs
514 Hojpitol Phormacy
INVENTORY POLICY— STORES
The first point usually considered in dis-
cussing msmtoncs is one of location Where
should the bulh-diug mvcntoiy items be
stored"^ \Vhat is the best storage place for
pharmacy supplies — in a general storeroom
or m a separate storeroom attached to and
part of the pharmacy?
Management experts all agree that, m gen-
eral, a common or central storeroom is ideal
Imentory is controlled and labor and record
keeping arc lessened by such a procedure
However, many well founded rules have ex-
ceptions, and pharmacy is the exception here
— there is no question that, in the interest of
economy and efficiency, there should be a
separate pharmacy storeroom under the com-
plete control of the Pharmacy Department
and as close to it as possible
In arriving at the policy that drug supplies
should be stored in separate pharmacy store-
rooms under the jurisdiction of the chief
pharmacist as against any dichotomous ar-
rangement mvolvmg general supplies, an
analysis is made of the factors of public
health and safety as well as those of efficient
and economy A few of these fundamental
considerations are the 4 following
1 Responsibility for storage of drags,
many of which deteriorate by improper stor-
age, IS given to those who by ihe« education
and training arc best quaLfied to assume this
responsibility
2 Rapid changes in drug therapy trends
and the prescribing habits of ph)sicians and
dentists usually are known immediately by
the pharmacist This information is not com-
monly held by other persons mvolvcd with
supplies. It IS necessary in properly deter
mining reorder amounts and/or the addition
and the deletion of stems in the drug m-
ventory
3 Such a system of operation gives im-
mediate availability and knowledge of per-
sons of supplies to the department which has
the sole authority to use the stock— the pbar-
mat^ department This ensures more efficient
service and lowers the amount of capital m-
vested in drug supplies as contrasted with the
amount of investment required m any other
sj'stcm It also couples with the responsibility
of maintenance of vital drug inventories the
necessary management compaiuon — account
ability
4 Stock-control and inventor) -cost rec-
ords are made by pharmaej pcrsoimel at or
dose to the time of the action, thus, lengthy
delays m postmg and preparation of requisi-
tions, as well as duplication of effort, are
avoided
This basic pattern for the control of drug
suppLes and stores follows principles laid
down by Malcolm T MacEachera, M D ,
former associate director of the Amcncan
Cbticge of Surgeons Dr MacEachera, m his
text on Hospital Orgamiation and Manage-
ment, slates that
in selecting a location it must not be for
gotten that ample xpace is required for bulk
storage and that this storeroom (pharmacy) is
preferably located on the ground floor close to
the pharmacy that the purchase of drugs
and pharmaceuticals is a specialty which can
be earned out to the best advantage by a phar
macist trained m managing a hospital phar
maty This is the only department m the
hospital m which it is usually not advisable to
have purchasing done by a general purchasing
agent
STOREROOM ARRANGEMENT AND
CONTROL OF STOCK
Dating ol Stocks. Sound business manage
ment indicates that money invested in drag
supplies be turned over 4 to 5 times yearly
This IS called “stock turn “ Normally, a stock
turn of less than 4 indicates an over-inventory
and of over S, outs * and shortages
Therefore, as the lint step m a program
of sound inventory control, all expendable
drug Items, when received into stores, should
be marked or stamped with the month and
the year of receipt For example, an item
received on February 15, 1956, should be
marked or stamped in small print “2/56 ”
The introduction of such a dating system
ensures the use of old stocks first and makes
more noticeable any overbuying on a par-
ticular Item
Drag-Stock Amuigcracnt. Drag supplies
maintained as stores (not expended to the
pharmacy proper, but kept in the pharmacy
storeroom) should be arranged in simple
alphabetical order with 5 exceptions
Perpe^uallnventory Records 515
1 Gallonage Gallon containers should
be arranged and maintained in alphabetical
order m a separate section or stored on
bottom shelves
2 Perishables such as biologicals, anti-
biotics and others should be stored m prop-
erly refrigerated units
3 Narcotics These should be stored in
properly locked containers that satisfy the
reflations of the Harrison Narcotic Act and
local authonties
4 Alcohol, Spirituous Liquors and
Wines TTiese should be stored m properly
locked, fireproof cabmets that meet the re-
quirements of the Federal codes and the local
taws, mcludmg fire regulations
5 Large Bulk Items Liter parenterals,
plasma, gases and others
"Shelf-Stripping" This consists of apply-
ing tape (the width of the rim of the shelf),
capable of carrying wntmg, to the upper front
edge of shelves The information and the
rulings on the tape indicate the “home” of
each particular item Each item is allotted a
definite width of the shelf for its accommoda-
tion Example
Acetylsalicylic
Acid Fuchsia
Agar
Acid
Tablets
325 mg
(4) 5 000
(1) lOGm
(2) LB
Information on the tape may give the name
(acetylsalicylic acid tablets), the strength, if
any (325 mg ) , the umt quantity (5,000), as
well as the minimum level (4) or reorder
pomt “Shelf-stnpping,” besides providing a
double check against shortages, ensures a
definite ividth of space on the shelf as the
“home” for the item The item is set directly
back of the tape m the space designated The
markmgs on the tape may be erased and
changed several times before a new tape is
required
PERPETUAL INVENTORY RECORDS
With drug stock systematically arranged
m a pharmacy storeroom, the task of setting
up and mamtaining a perpetual inventory
sj’stem becomes fairly simple For this pur-
FiG 205 Biological stock control form
(USPHS)
pose, use of a visible Kardex or similar type
drawr file appears to offer the ideal solution
This system provides a standard method
of controlling stock levels, ensurmg avail-
ability of supplies, the reportmg of drug-
usage rates and a monthly mventoty value on
each Item stocked Inasmuch as current sta-
tistics indicate that 25 to 33 per cent of every
supply dollar at a hospital goes mto drug
purchases, the value of sound records m the
pharmacy department cannot be underesti-
mated
Operation of Inventory Control System.
Normally, the chief pharmacist places the
responsibility of postmg to the stock cards
and the accuracy of the records, including
ihe accuracy of inventory and the correction
of extensions, on one person, usually a com-
petent pharmacy helper This person is given
the responsibility for drug receipts, with-
drawals, perpetual inventory records and
storeroom arrangement m addition to his
other duties In practice, it has been found
that, when the pharmacy helper has been
properly selected and trained, he is well
quidified to assume this responsibility Obvi-
ously, m one-man pharmacies, this responsi-
bility must rest on the pharmacist himself
TTie person made responsible for the
pcnodic checking of physical stocks against
the perpetual inventory records should be
instructed to check items m at least 2 letters
of the alphabet weekly, le , A and B items
one week, C and D items the next week and
so on Neat stock arrangement, clean, dust-
free storeroom, and accurate unit and exten-
sion cost records in the perpetual inventory
osually result when such a check system is
516 Hospital Pharmacy
cmplojcd Furthermore, such a check system
gives, annually, 4 complete ph)sical checks
of supplies against records plus the usual
official ph)'sical inventory taken at the close
of the fiscal) ear
Some hospitals have found it convenient
to locate the stock-control records just mside
the entrance of the pharmacy storeroom
where poslmgs of inflow and outflow of stock
may be made at the time of the action
Purchase requests for supplies usually arc
prepared when the minimum or reorder
point IS reached on the stock-control cards
however, in determining reorder amounts
and/or the addition and deletion of items
from the drug inventory, such factors as
drug-therapy trends and changes in medical
and dental staffs also must be taken into con-
sideration As a rule, except in emergencies,
purchase requests for supplies are submitted
to the Purchasing Department on certain
designated days Purchase requests should be
dated and prepared in duplicate with the
carbon retained m a “requisitions pcoding”
file in the pharmacy Copies of purchase
orders issuca for pharmacy supplies by the
hospital should be routed to the pharmacy
where they are stapled to copies of the
requisitions This material is kept m an
“orders pending" file until receipt of the
stock, at which time it is filed for the duration
of the fiscal )car in the contractor’s folder
on file m the pharmacy
It will be noted that items expended from
the storeroom to the pharmacy proper arc
not included in the inventory value Tlie
value of such items may be kept at a constant
figure for a 12-month penod, when a new
physical inventory provides the adjustment
betor ^Vhile it is admitted that this is not
an accurate inventory figure, for 1 1 months
out of the 12, It IS correct as of the last
month of each fiscal )ear and does not im-
pose the cost of an expensive physical in-
ventory of open stock each month
A QUARTERLY AND ANNUAL
REPORTING SYSTEM FOR CO^TS
AND WORKLOADS
It IS the responsibility of chiefs of phar-
maceutical services to provide the adminis-
trator with a quarterly or monthly and )cariy
yanlstick with which to measure depart-
mental aciivi^ and progress
This report is one of the major tools of
mana^ment Tlirough it, a department head
documents his needs for a larger or a smaller
budget, for increased or decreased personnel,
for equipment and for other needs
A hospital might well adopt a combmation
profcssional-business-type report In such a
report, the quarterly or monthly professional
workload factors could be divided into in-
patient and outpatient activities The work-
load might be broken also into various cate-
gories, such as those requumg special
accounting as made necessary by Federal and
state laws (narcotics and ethyl alcohol), and
those categories not entailing extra man-
hours of bookkeepmg
In brief, the workload of the pharmacy is
presented as a report of specific areas of
major activity Each prescription, requisition
or issue to a ward or a clinic and each manu-
factured Item and item prepackaged is tabu-
lated
Space may be provided in the quarterly or
monthly workload report for reporting phar-
ma^ committee meetings and their activities,
as well as space for remarks on pharmacy ac-
tivities of the quarter or the month, such as
climcal pharmaceutical research, new equip-
ment received, papers prepared for publica-
tion, drug therapy consultant activities and
other matters
Finally, the reporting system should pro-
vide for noting the number of group meet-
ings, both intramural and extramural This
IS a valued part of the report inasmuch as it
covers ‘nonmeasurable workloads ” In hos-
pital pharmacy, considerable time is devoted
to * nonmeasurable" loads such as individual
consultations on drug therapy problems with
medical, dental and allied personnel, hospital
pharmacy indoctrination and teaching sched-
ules for medical and dental interns, nurses
and hospital aides, also man hours arc con-
sumed m the requisitioning or purchasing of
supplies, the keeping of perpetual narcotic,
hypnotic, gram alcohol and spintuous-Iiquor
inventories, the preparation of the quarterly
or monthly reports on stock control, drug
costs, workloads, indoctnnation and teaching
of junior hospit^ pharmacists and, m some
utstanccs, senior pnarmacy students, as well
Fto 206 Quarterly report of pharmacy operations, parts I II and III (U S P H S )
15101
Fio 206 {Continued) Quarterly report ot pharmacy operations, parts IV, V and VI (USPHS)
Fio 207 Annual recap sheet parts I and II (USPHS)
I 520 I
Fio 207 (Continued) Annual “recap” sheet, pans III, IV, V, VI and VII (USPH,S)
I U? ]
522 Hospital Phormocy
as time spent m attendance and preparation
for staff and pharmacy committee meetings
Total personnel is reported in Part III of
the monthly or quarterly report form (Fig
206, top and bottom) used to illustrate the
reporting system described All personnel
assigned to the department, esen though part
of their time is spent m other areas, are re-
ported with this system This serves to brmg
to the attention of the administrator the
added responsibilities of pharmacy person-
nel m nonpharmaccutical duties
Value of Reports. In the quarterly or
monthly report, the hospital administrator
has a yardstick or measurement tool of the
pharmacy department, he knows quarterly
or monthly and annually (see annual “recap ’
sheet, Fig 207, top and bottom) the pro-
fessional workload, the committee activities
and the personnel structure, as ucll as the
pharmacy's inventory status, inventory or
• stock turn,” the average cost of medications
per outpatient visit, the average cost or value
of inpatient medications per inpatient day
and the average cost of each prescription
Nothing 1 $ left to guess or estimates Should
a department need increased manpower, one
has documented proof of (he need Should
the administrator be required to cut back on
budgeted funds, one again has proof of
actual drug needs based on usage rates —
proof that (he pharmacy budget fund can be
released to other areas or that pharmacy
funds cannot be cut if normal service flow i$
to be maintained To aid m the recording of
the statistics indicated in this type report, a
daily worksheet is utilized (sec Fig 208)
automation
Hospital pharmacy practice— like other
hospital activities must expect increased
automation in the future Automation that
ensure more clTicicnt service at less cost with
no loss of patient safety and drug control is
to be encouraged However, any automation
that violates the practice acts and regulations
of medicine, nursing and pharmacy may leave
the hospital, the administrator and the oper-
ator of the equipment open to censure and,
possibly, legal action
In this connection, il is necessary that
drug dispensing — (a function of pharma^)
and drug administration (a function of nurs-
ing) be cleariy understood
Drag dispensing is a function that is by
custom, tradition and law restneted to
licensed practitioners of pharmacy. Drug dis-
pensing involves the issuance of one or more
doses of a medication m containers other than
the ongmal, such containers being properly
labeled by the dispenser as to contents and/or
directions for use as indicated by the pre-
senber Drug dispensing Includes also the
issuance of a medication in its ongmal con-
tainer with a pharmacy-prepared label at-
tached, the label carrymg the signa of the
presenber as well as other vital information
Drug dispensmg also mvolves situations in
which the package carries a pharmacy-pre-
pared label and is intended for nursing station
use m a hospital or a nursing home Ihc con-
tents of the container may be for one patient
(such as an individual prescription) or for
several patients (such as a floor stock nursing
stations medication container)
For patient safety, the ideal situation m
drug dispensing is one m which the medica-
tion order, in the handwriting of the pre-
scriber, is presented to the pharmacist for
compounding and dispensmg However, until
this Utopia IS reached, floor stocks and medi-
cation orders "transaibed’ by nurses are
the traditional avenues used m hospital drug
and medication distribution systems
Drug odministrnlion is a nursmg activi^
by which a smgle dose is administered to the
patient by the nurse on the order of a physi-
cian or a dentist
The filling or the refilling of a nursmg sta-
tion medication container wifn &c drug
called for is “drug dispensing” and can be en-
gaged m legally only by a licensed pharmacist
under the Pharmacy Practice Act and the
regulations of the several states
The public health point at issue concerns
patient safety and error control Should a
nurse remove a single dose from a wrong
contamer the damage is confined to the pa-
tient m her cliargc However, should the
nurse perform an act restricted by law to
(rained pharmacists (drug dispensing), such
as the rcQIlmg of a patient’s prescription or a
floor stock medication contamer, it is possi-
ble that an error may injure all patients who
subsequently receive medication from that
Bibliography 523
container, whether the medication is “admin-
istered’ by the nurse making the error or
other nurses on duty at the medication center
where the contamer is housed
One must study automation activities m
this light automation equipment that be-
stows ‘drug dispensing” rcsponsibUiUes on
nurses, or ‘ drug administration” activities on
pharmacists is, quite likely, illegal under the
laws of the states Such equipment places in
the hands of individuals responsibilities which
they have not been trained to handle For ex-
ample, nurses are tramed by formal study
and expenence in “drug admmistration,” i e ,
to observe m the givmg of a medication the
outward signs of reactions such as changes
m respiration, pulse and myotic or mydriatic
reactions Pharmacists, on the other hand,
are trained m drug evaluation, selection, stor-
age, identification, compounding and dis-
pensmg characteristics The following prac
tice would quite likely be m violation of state
laws and regulations if a nurse should pla(»
a label on a medication contamer or other-
wise identify the container as prepared for a
particular patient when the amount of the
medication is in excess of the number of
doses to be administered by that nurse dur-
mg her 8-hour tour of duty, such an act
would be drug “dispensing ’ and not drug
“administration ’’
RESIDENCIES
A Phannacy Residency m a hospital is a
postgraduate progcam. of ocgatuzed tcaioiag
approved by the American Society of Hos-
pital Pharmacists The trammg must consist
of not less than 2,000 hours extended over
a period of at least 50 weeks to meet the
A^ H P Accreditation Standards (or Rest
dency m Hospital Pharmacy as approved in
May, 1963
Residencies m hospital pharmacy may be
given only in general hospitals accredited by
Die Jomt Commission on the Accreditation
of Hospitals
The areas of activity of the residenqr cover
administration, inpatient and general dis-
pensing, outpatient dispensing, formulation,
preparation and control of sterile pharma-
ceuticals, and formulation, preparation and
control of nonstenle pharmaceuticals
Usually, the residency consists of a senes
of lectures, conferences and practical expen-
ences covermg all phases of hospital phar-
macy In addition, the pharmacy resident
rotates among the other departments of the
hospital, such as mtemal medicine, surgery,
pathology, radiology, nursmg and administra-
tion He participates m stag and committee
discussions, seminars and demonstrations and
works with mtems from other services on
]omt studies The resident gams firsthand
knowledge of the professional and the man-
agement activities that compnse the total
hospital function, with special reference to
drug evaluation, selection, procurement and
utilization and, also, to clmical drug studies,
drug movement and control Also, during the
year, each resident is assigned a pharmaceu-
tical problem for investigation on which he
IS expected to write a thesis
BIBLIOGRAPHY
Aroencan College of Surgeons Manual of Hos
pital Standardization, 1946
American Hospital Association The Magic
to Hospital Literature
Statement of principles on the use of
investigational drugs m hospitals, Hospitals,
January 1 1958
The hospital formulary system, Hos
pitals, October 16 1960
— — Guide Issue, Hospitals August 1,
1962
Editorial Notes — ^Formula for formu
lary. Hospitals, July 1, 1963, p 23
Amencan Society of Hospital Pharmacists
Minimum standards for pharmacy intern-
ships in hospitals with guide to application,
as amended November 8, 1962, Am I Hosp
Pliarm In Press
Accreditation standard for residency
in hospital pharmacy, May 11, 1963, Am J
Hosp Pharm In Press
Statement on the abilities required of
hospital pharmacists. Am J Hosp Pharm
19 493, 1962
Constitution and bylaws, as revised
1962, Am J Hosp Pharm 19 423-428,
1962
Aicbambault, G F Hospital phannacy as a
career, Sci Counselor J7 61,1954
A narcotic control system for the gen-
eral hospital. Hospitals 28 1 12, 1954
Procedural manuals for hospital phar-
macies, Am Prof Pharmacist 19 42, 1953
Hermetically packaged surgical fluids,
Pharm. Intemat 6 35, 1952.
524 Hasp fol Phormocy
Practical appl cations of mmimum
standards (in 3 parts) Hosp Prog 33 SO
33 80 33 84 1952
The business s de of hospital phar
mac} Bull Am Soc Hosp Pharmacists 9
102 1952.
— Standards for prescription containers
Bull Am Soc Hosp Pharmacists 8 103
1951
Arthur W R Law of Drucs and Drucgists
ed 3 St Paul Minn West 1947
Bierman C H and Archambault G F The
hospital pharmacy from the administrators
point of view Hosp Management 57 86
1944
Drawback on Tax on Distilled Spints Used m
Manufacturing of Non Beverage Products —
Regulation No 29 US Treasury Depart
ment Bureau of Internal Resenue 1947
FitzGerald E J and Archambault G F The
Publ c Health Service Bull Am Soc Hosp
Pharmacists 9 270 1952
Food and Drug Administrat on Service and
Regulatory Announcements — Food Drug
and Cosmetic No 1 Revision No 3 Depart
ment of Health Education and Welfare
Francke O Evaluation of management guides
Hosp Progress p 94 September 1954
Goodness J H Personal communications
Guild of Publ c Pharmacists Hospital Phar
macy Planning ed 2 London 1961
Harrison Narcot e Act— Regulal on No S and
Supplements (1949) US Treasury Depart
ment Bureau of Narcotics
H mmcisbach C K. and Nelson k The Rc
sponsibditics and Functions of the Individual
Pharmacy Committee Mcmbcn US Public
Health Service D vision of Hosp tals Circular
Memorandum No 54-130 March 1954
Hogan T J and Archambault G F Meeting
problems of design in hospital pharmacy
Bull Am Soc Hosp Pharmacists 10 293
1953
Hope M C The hospital surscy and constrtK
lion program Am J Publ Health 39 7
1949
K)ait H}3tl and Croeschel Law of Hosp tal
Physician and Psticnt ed 2 New York Hos
pital Teal Book 1952
Industrial Alcohol US Treasury Department
Bureau of Internal Resenue Regulation No
3 (1942) and Supplements
Jeffnes S B A new approach to costing and
pricing prescriptions in the hospital phar
macj Bull Am Soc Hosp Pharmacists 11
455 1954
Joint Commission on Accreditation of Hospitals
— Standards for Hospital Accreditation De
cember 1953
MacEachem M T Hospital Organization and
Management Chicago Physicians Record
Co 1940
McGibony Pnnciplcs of Hospital Administra
tion New York Putnam 1952
Marihuana Act — Regulation No 1 (1937),
U.S Treasury Department Bureau of Nar
cotics
Petit W Manual of Pharmaceutical Law New
York Macmillan 1951
Regan L J Doctor and Patient and the Law
ed 2 St Louis Mosby 1949
Registration of Stills — Regulation No 23 U.S
Treasury Department Bureau of Internal
Revenue
Skolaut M Scigiliano J and Salvma J The
central sterile supply of a pharmacy depart
ment Bull Am Soc Hosp Pharmacists 2
114 1954
Sloan R P This Hosp tal Business of Ours
New York Putnam 1952
Traulman J Masur J and Archambault
C F Facil ties for pharmaceutical service
Clinical Center National Institutes of Health
Bull Am Soc Hosp PharmacistsP 38 1952
U.S Government Printing Office Operations
of the United States Marine Hospital Service
1896
U S Public Health Service Hospital Services
1953 Pharmacy Bull Div Hosp Facilities
Will ams R C The United States Public
Health Service 1798 1950 Bethesda Md
U.S Publ Health Service 1951
Zugich J J Pharmacy Hospitals 27 No 6
Part II June 1953
Monthly reports emphasize value of
pharmacist to hospital Bull Am Soc Hosp
Pharmacists 2 64 1945
Note A comprehensive indexed bibliography
on hospital pharmacy has been prepared by the
American Society of Hospital Pharmacists It
covers all facets of hospital pharmacy The stu
dent IS referred to this bibliography for addi
tonal reference material (see Bull Am Soc
Hosp Pharmacists 8 No 1 January 195!
and supplements)
chapter 14
Radiopharmaceuticals
William H. Briner,* Commander, U S. Public Health Service
HISTORY
While the use of radioactive materials to
study and treat some of the ills of mankind
IS not particularly new, the emergence of
radiopharmaceutical products as an im
portant part of the Araencan medical scene
has come about largely as a direct result of
the weapons technology of World War H
Radium”* and its radioactive daughter
radon®” had been widely used to treat a
variety of pathologic states both in this
country and abroad for nearly 40 years be-
fore the begmning of World War 11 In addi-
tion, early m 1936 Dr Joseph G Hamilton
undertook the first studies of sodium move-
ment m the body, using the radionuclide
sodium” which had been produced in the
c)clotron at the Berkeley campus of the Uni-
versity of California®® Following this, a
number of investigators throughout the world
performed studies of thyroid metabohsm and
active lodme derived from particle accelera-
tors
Then m December of 1942, occurred an
event so remarkably significant that its im-
portance IS not understood by many people
even today The incident was, of course, the
production of the first controlled chain re-
action, This took place m an atomic pfle
composed of graphite bricks, fueled with
natural uranium located on a squash court
beneath Stagg Field at the Umversity of
Chicago This first successful expenmeot in
• Chief, Radiopharmaceutical Service, Pharmacy
Department, Clinical Center, Kation4 Institutes
of Health. U S Public Health Ser\ice U S De
partment of Health. Education and Welfare
Bethesda, hid
the cnticahty of piles, or reactors, was
directed by the Italian bom physicist, Enneo
Fermi The ultrasecret Manhattan District
then developed more sophisticated nuclear
reactors for the production of fissionable ma-
terial to be used in atomic bombs
A very necessary part of this research was
a consideration of certain by-product mate-
nai known as radioisotopes, which was pro-
duced m these reactors After hostilities bad
ceased, this by product roatenal was diverted
to civilian uses, including certam medical ap-
plications — and the first radiopharmaceutical
products as i^e know them today began to
appear
PHILOSOPHY OF A
RADIOPHARMACEUTICAL SERVICE
In the early days of research m nuclear
medicme, it \^'as extremely difficult for a
pharmacist to participate or assist in such
endeavors — ani mdeed, few pharmacists ex-
pressed any mterest m these problems How-
ever, m the ensuing years, durmg which time
phannaceulical products containing radio-
active constituents have become firmly estab-
lished m value and usage, pharmacists have
become more acutely aware of their abihties
and responsibilities m this area of practice
Monographs for radiopharmaceutical prod-
ucts now appear m the Pharmacopeia of the
Umted States,®* and additional monographs
for such products are to be found in New
and NonoSicial Drugs ” Thus, there would
seem to be httle need to justify the mterest or
participation m radioisotope procedures by
pharmacists Too frequenUy, however, cer-
tam professional deficiencies are given too
525
57 6 Rodiopharmaceulkolf
much emphasis by nonpharroacy personnel
m evaluating the abilities of pharmacists in
these areas For example, it is true that very
few pharmacists arc also nuclear ph)sicists
or radiation chemists It is also true that most
pharmacists are not doctors of medicme
Hoi^cvcr, the latter fact docs not prohibit
some of them from professional pracDce in-
solving the formulation of injectable products
used by physicians in their practice
The important point to remember is that
some additional training is usually required
no matter what facet of specialized practice
a pharmacist may choose, whether it be in-
jectable formulation in industry or hospital
pharmacy practice, tcachmg, radiopharma-
ceutical practice, or any one of a myriad of
avenues of specialization open to a graduate
pharmacist This additional period of train-
ing may well be reduced both in scope and
in duration if the present trend toward more
and more instruction in schools of pharmacy
in radioisotope technics contmues Christian**
noted m 1960 that 18 schools were utilizing
radioisotopes in their teaching programs. 15
of these olTcrcd specific instruction m isotope
technology, while the remaining 3 made use
of such material m courses such as pharma-
cology or quaotitauve analysis In addiuon,
21 schools were, at that time, making use of
such compounds in research This study also
mdicated that, of the schools of pharmacy not
oflenng a rourse m isotope technology at
that tune, 23 mdicated that they planned to
offer such a course within the foUowmg 2
years and that, up to the tune of the report
cited, some 1,788 students m schools of phar-
mey had leecwcd sadicwsotopc tnisung
Although commercial suppliers now offer
B wide range of radiopharmaceutical prod
ucts for clmicians who arc authorized to re-
ceive them, frequently, there still exists a
need to modify or change the commercially
available product to meet more closely the
needs of an mdividual user or patient In
many cases, this change may consist merely
of an aseptic dilution of the commercial
product At times, however, the modiflcatioo
is considerably more complex. In either case,
a pharmacist who is well trained m radio-
isotope technics and radiological health is
able to contribute much in this area if be will
only apply his knowledge
The need for such expert pharmaceutical
assistance becomes mandatory when radioiso-
topes are procured for use m human subjects
from other than a reputable pharmaceutical
supplier It IS a standard condition of the
Umied States Atomic Energy Commission
that the licensee must show proof of his
ability, or the ability of someone in his m-
stitution, to attest to the pharmaceutical
quali^ of such materials No one is better
able io attest to pharmaceutical quali^ of a
given matenal than an appropriately trained
pharmacist
These, then, are only a few reasons why it
IS becommg more and more necessary for
pharmacists to assist m this new area of
practice
TYPES OF RADIOACTIVITY
Radioactivity is customarily divided into
two different types these are natural radio-
activity and artificial radioactivity Radio-
activity itself has been defined* as the several
processes by which atomic nuclei sponta-
neously decay or disintegrate by one or more
discrete energy levels or transitions until,
ultimately, a stable state is reached When
such events take place m a material without
the addition of energy, the substance is said
to be naturally radioactive Artificial radio-
activity, often called * man made radio-
activity,” may be described** as the property
of radioactivity produced by particle (wra-
bardment or electromagnetic irradiation —
the radioactivity of synlheuc nuclides
Natural Radioactivity
The first reported evidence of natural
radioactmty appeared in 1896, as a result of
Henri Bccquercl’s discovery that a shielded
photographic plate is darkened when exposed
to uranium ore, m much the same way as a
film reacts when exposed to x rays There
arc more than fifty known naturally occumng
radionuclides, examples of which mclude
uranium***, thorium"**, radium***, actm-
lum***, Icad*‘*, and potassium*®
Artificul RADioAcnvmr
Artificial radioactivity may be produced In
a variety of ways, and m any of several de-
vices, dejKoding on what bombarding par-
Types of Radioactivify 527
Table 99 Elements Determined in Trace Quantities
BY Neutron Activation Analysis*
Element
Bismuth
Calcium
Iron
Magnesium
Nickel
Niobium
Silicon
Sulfur
Tjtamum
Cenum
Chromium
Mercury
Molybdenum
Neodymium
Platinum
Ruthenium
Silver
Strontium
Tellurium
Thallium
Tin
Zirconium
Aluminum
Banum
Cadmium
Cesium
Chlorme
Cobalt
Erbium
Gadolinium
Germanium
Hafnium
Osmium
Phosphorus
SENSmVITV
OP Detection
(g>
io-«
Element
Potassium
Rubidium
Selemum
Thorium
Yttrium
2iac
Antimony
Arsenic
Bromine
Copper
Gallium
Gold
Iodine
Lanthanum
Palladium
Praseodymium
Scandium
Sodium
Tantalum
Terbium
Thulium
Tungsten
Uranium
Vanadium
Ytterbium
Holmium
Indium
Indium
Lutetjum
Manganese
Rhenium
Samanum
Europium
Dysprosium
Sensittvity
OF Detection
(g)
10 -“
• From Radioisotopes — Special Materials and Services Ird revision 1960 Oak Ridge Nauonal Labo
ratory, operated by Union Carbide Corporation for the U S Atomic Energy Commission
tide or ray is utilized In general, these
nuclear reactions are categorized as charged
particle, photon or neutron mduced reactions
In the examples of each which follow, the
subscript refers to the atomic number of the
element, often called the Z number, wMc
the supersenpt denotes the atomic mass num
ber of the isotope, and is often referred to
as the A number It should be noted that
the subscripts and the supersenpts on each
side of the equations balimce, m much the
same manner as ordmaiy chemical equations
are balanced
Charged Particle Reactions. Reactions of
these types may be produced with protons
(illustrated symbolically as iH* or p),
demerons (iH® or d), alpha particles (jHe*
or «), or, occasionally, by electrons or beta
particles (_ie°or_j/?®)
A Proton initiated Reaction
iH‘ + iiNa«-»„Mg» + oa®
52S Rodlopharmoceuticolt
In this reaction, nonradioactise sodium is
bombarded with protons to form magne-
sium*’, the reaction also jidding a neutron
(on*)
A Deutfron-induced Reacthn
An Alpha particle-tmiiated Reaction
,hn‘ + :He* sQ” -f- ,H‘
rhoton*1nduccd Reactions. Electromag-
netic radiations or photons of high energy
may also induce nuclear reactions, as the
following example ilustrates
y-f-4Bc»-+4Bc*4-oO^
The source of electromagnetic energy utilized
in this t)pc of reaction may be a gamma-
cmitting radionuclide, os m the example
cited, or a high voltage x ray generator
Ncutron-Tnduccd Reactions. One of the
most important and, also, most widely used
methods of producing artificially radioactivx
nuchdes is the bombardment of a non
radioactive target nucleus with a source of
thermal neutrons An example of such a re-
action IS the production of radioactive so-
dium** by neutron capture m sodium’’
„Na« + oH’ -♦ iiNa’* + y
Another extremely important use of this
type of reaction is m the relatively new
method of chemical analysis known as neu-
tron activation anal}'sis In this application,
radioactivity is induced in a sample of un
known chemical composition by exposing the
sample for a given period of tunc to a neutron
flux At the conclusion of the exposure
period, the sample is removed from the neu
tron source, and the induced radioactivity is
determined both qualitatively and quantita-
tively by means of suitable radiation ana-
IjTcrs As IS apparent from Table 99, this is
an extremely sensitive method of analysis
RADIOACTIVE DECAY
Radioactive species by definition exist in
a highly cxciicd, unstable state, charactenzed
by an energy excess These nuclides ulti-
mately achieve stability through the process
of radioactive decay and the release of large
amounts of energy, cither kinetic or electro-
magnetic or both of these types simultane-
ously In this process of decay there arc three
parameters which are charactenstic of a
given radioisotope Indeed, identification of
unknown radionuclides is based on these
three properties the rate of decay, the
typc(s) of radiation exhibited in the decay
scheme, and the energies of these radiations
The rate of decay of a radioisotope is in
dicated by the number of atoms of the nuclide
which arc disintegrating per umt time This
number is proportional to the total number
of radioactive atoms present in the sample, as
IS evident from the following relationship
AN = — ANAt, where AN is the number of
atoms disintegrating per unit time At, and N
IS the number of radioactive atoms present
The symibol X is the decay constant The
negative sign in the equation is used to in-
dicate that the number of atoms is decreasing
with the passage of time By integratmg this
equation the more familiar mathematical re-
lationship often known as the decay equation
IS denved
N = NoC-«
where N is the number of radioactive atoms
present at time t, and No is the number of
atoms originally present at tune zero The
decay constant lambda, may be defined** as
the fraction of the number of atoms of a
radionuclide which decay m unit time The
use of the decay equation is appropnatc only
if there IS a sufilciently large number of
radioactive atoms present at t = O to make
the relationship statistically valid That is
to say. It IS impossible to determine when
any one radioactive atom m a given sample
will dismtegrate, but, if there is a statistically
large number of such atoms present, the frac-
tion of the total which is disintegrating per
unit time can be predicted with a high degree
of accuracy In actuality, the statistical
reUabihty of an observation is given by the
standard deviation, s, where
s = N*‘
in which N is the number of observed disin-
tegrations Thus, radioactive decay is a typi-
cal first-order reaction
The physical half life of a radioisotope,
noted symbolically as T**, is defined as the
Radioactive Decay 529
Table IOO Decay Table for Au”®*
(A factor (30 minutes) =0 00537, Tj = 2 69 days or 64 6 hours)
Hours
0
05
10
1 5
20
25
30
35
40
45
0
9946
9893
9840
9787
9735
9683
9631
9579
9528
5
9477
9427
9376
9326
9276
9226
9177
9128
9079
9030
10
8982
8934
8886
8838
8791
8744
8697
8650
8604
8558
15
8512
8466
8421
8376
8331
8287
8242
8198
8154
8110
20
8067
8024
7981
7938
7896
7853
7811
7769
7728
7686
25
7645
7604
7564
7523
7483
7443
7403
7363
7324
7285
30
1246
7207
7168
7130
7092
7054
7016
6978
6941
6904
35
6867
6830
6793
6757
6721
6685
6649
6613
6578
6543
40
6508
6473
6438
6404
6369
6335
6301
6268
6234
6201
45
6167
6134
6102
6069
6036
6004
5972
5940
5908
5876
50
5845
5814
5783
5752
5721
5690
5660
5629
5599
5569
55
5539
5510
5480
5451
5422
5393
5364
5335
5306
5278
60
5250
5222
5194
J166
5138
5111
5083
5056
5029
5002
65
4975
4949
4922
4896
4870
4844
4818
4792
4766
4741
70
4715
4690
4665
4640
4615
4590
4566
4541
4517
4493
75
4469
4445
4421
4397
4374
4350
4327
4304
4281
4258
80
4235
4212
4190
4167
4145
4123
4101
4079
4057
4035
85
4014
3992
3971
3949
3928
3907
3886
3866
3845
3824
90
3804
3783
3763
3743
3723
3703
3683
3663
3644
3624
95
3605
3586
3566
3547
3528
3509
3491
3472
3453
3435
100
3416
3398
3380
3362
3344
3326
3308
3290
3273
3255
105
3238
3220
3203
3186
3169
3152
3135
3118
3102
3085
no
3068
3052
3036
3019
3003
2987
2971
2955
2939
2924
115
2903
2892
2877
2862
2846
2831
2816
2801
2786
2771
120
2756
2741
2727
2712
2697
2683
2669
2654
2640
2626
125
2612
2598
2584
2570
2556
2543
2529
2516
2502
2489
130
2475
2449
2423
2397
2371
135
2346
2321
2296
2272
2247
140
2223
2200
,2176
2153
2130
145
2107
2085
2062
2040
2018
150
1997
1976
1955
1934
1913
155
1892
1872
1852
1832
1813
160
1794
1774
17S5
1737
I71S
165
1700
1682
1664
1646
1628
170
1611
1594
1577
1S6D
1543
175
1527
1510
1494
1478
1462
180
1447
1431
1416
1401
1386
185
1371
1357
1342
1328
1314
190
1300
1286
1272
1258
1245
195
1232
1218
1205
1193
1180
200
1167
1155
1142
1130
1118
205
1106
1094
1083
1071
1060
*From Radiological Health Handbook PB 121784R U S Department of Health Education and
Welfare USPH5 Washington. 1960
tune interval during which half of the radio- active decay, although m a somewhat differ-
active atoms ongmally present m a sample cnt manner Their mathematical relationship
will have decajcd There is a close relation- is shown by the equation
ship, both theoretically and inathematicaDy, q ^
between phj’sical half life and decay con- 1^= —
stant, for they both indicate rates of radio-
530 Radiopharmoceuticalj
The basic decay equation is extremely use-
ful, for, by substituting m the basic equation
as follow, both the activity (A) remaining
m a sample after a given time and the in-
tensity 01 radiation (I) after ume t can be
determined
A = A,c-® or I =1^-® wsv**
\Vhne these s'alues can alisays be computed
usmg the relationships given above, decay
tables for many of the more commonly used
medical radioisotopes are reproduced to most
standard reference books Table 100 show a
typical table, mdicating the decay of the
radionuclide gold***
Modes of Radioactive Decay
There are a number of methods by which
radionuclides decay or disintegrate to ground
state These modes include alpha particle
emission, beta particle (negatron) emission,
positron (positive beta particle) emission,
electron capture, internal transition and cer-
tain conversion moccsses Examples of some
of these method of decay will be given in
the follov.ing sections
Alpha Particle Decay. An alpha particle
IS composed of two protons and two neu-
trons and has been ideniifled as the nucleus
of the helium atom S)’mbolicaUy, an alpha
particle is wilten jHe*, and, since there are
two protons present, the particle has a double
positive charge The general equation sig-
nif) mg or defming alpha decay is
.X^-*^aY^-'-|-:He‘ + Q
where X is the parent radionuclide, Y the
daughter resulting from that decay, and Q the
energy required to make the reaction go. or
the energy released os a result of the reac-
tion. Substituting actual elements lo the cqua
tion, V, c can indicate the process by which the
uranium isotope of mass 23S decays
,.ir»-Mni“* + sHc* + Q
In alpha decay, since 2 protons are lost, the
atomic number dcaeascs by tno, and, smee
4 atomic mass units are ^so emitted, the
mass number of the daughter is also de-
creased by four It can tw derived maihc-
maticall) that the magnitude of the Q in this
equation is something in excess of 4 million
electron volts (Mev )
Bela Particle Decay. ^Vhen beta particle
emission is mentioned without further quali
fication, It can be assumed that negative beta
particles are being considered However, in
the strictest sense beta emissions would also
include positive beta particles, which will be
discussed 10 the next section
Negative beta particles have often been
compared with— or, indeed, identified as —
electrons which ongmate in the nucleus This
definition is satisfactory for purposes of dia-
grammatic representation of certain nuclear
reactions However, it implies that there arc
free electrons present in the nucleus, and it
has been shown that this condition docs not
occur
Andrew* has described negative beta par-
ticle emission as the conversion of a nuclear
neutron to a proton just before emission,
according to the equation
on* -*• ip* +
As IS apparent, this reaction would mcrease
the atomic number by one, while leavmg the
total number of nuclear particles unchanged
— conditions which arc known to be the case
IQ negauve beta emission
The general equation for beta decay is
Substituting the isotope of phosphorus with
a mass of 32 in the above equation, we have
an example of a pure beta decay
Posilron Decay, The general cqvatton de-
noting decay by positron cmbsion is*
i:X*-»t_iY*+ +1/3® 4- Q
Tbc daughter product of such a reaction is
less positive by one unit of charge, and the
mass number remains unchanged An actual
example of a radionuclide which decays by
positron emission is
„Ni”->„Fc»^-f-+,/r*4-Q
In both the positive and the negative beta
decay reactions, it can be shown that an ap-
parent energy discrepancy results in the sim-
ple equations shown for these reactions,
Units of Radioacfivify 531
unless some other particulate emanation is
present m these transitions This is m fact
the case, for, m negative beta emission, a
particle identified as a neutrmo (electrically
neutral and of extremely small mass when
compared with the mass of the beta particle)
IS present m the reaction as shown below
zXA->2 + iY^ + -i/3'* + v + Q
where the Greek letter Nu mdicates the pres-
ence of the neutrmo m the reaction.
In the case of the positron emitter, the
equation becomes
^^^z-iYA-{-+iP« + v+Q
where Nu again mdicates the presence of an
additional particle, this time known as an
antmeutnno The antmeutnno, like its coun-
terpart the neutrmo, amounts for the energy
surplus m the reaction, has no charge and has
a very small rest mass
It should be mentioned that, aldiough only
pure beta emitters have been outimed m the
examples cited for positive and negative beta
decay, there frequently is a mixed beta-
gamma decay scheme encountered m actual
practice An excellent example of this type
of decay scheme, and one which is frequently
seen in ndiophannaceutical practice, is m
the decay of the radionuclide sodium^^, this
isotope dec^s by negauve beta emission to
magnesium,** with the concurrent emission
of two energetic gamma rays of 1 38 and
2 76 Mev , respectively, as shown m the fol-
lowing general equation
iiNa« isMg=* + + 7 + Q
In the case of either positive or negative
beta decay, particles are emitted from un-
stable nuclei with a continuous energy spec-
trum, ranging from nearly zero to a maximum
beta energy listed m isotope tables for each
radionuclide A rule of thumb, m cases where
the mean beta energy for a given transition
IS not known, is to assume the mean beta
energy to be that of die maximum listed
m the tables In actuality, these means range
m value from 0 2 to 0 4 of the maximum
Orbital Electron Capture. The most fre-
quent electron capture reactions mvolve the
K shell In this case, the nucleus of a radio-
nuclide absorbs an electron from the K shell.
and, m so domg, neutralizes a proton m the
nucleus It is apparent from the general equa-
tion given below that the products of such a
reaction, are the same as though a positron
had been emitted
zX^-^-ie^-^z-iY^-I-hv
Tlie equation mdicates that one of the prod-
ucts of this reaction (hv) is electromagnetic
radiation (or photons) which can be pro-
duced either as gamma rays or x rays An
example of a frequently used radioisotope
which d«ays by orbital electron capture is
the nuclide chroimum®^, whose decay equa-
tion IS
2iCrS‘-f _iC»->23Vsi-f-hv
Another useful means of indicating the
decay reactions which take place with a given
radioQuchde is in the diagrammatic repre-
sentation of the decay scheme In the case
of chromium,^' the decay scheme might be
diagrammed as follows
27 8 days Cc«‘
Other examples of decay schemes and, m-
deed, a whole host of other nuclear data are
to be found m the Table of Isotopes **
UNITS OF RADIOACTIVITY
It IS difficult to describe anything without
havmg the means with which to describe it
and some baseline with which it can be com-
pared In the case of radioactivity, one must
become thoroughly familiar with the systems
of umts which are used to characterize nu-
clear radiations and their effects m media
throu^ which they traverse and with which
they react
Of greatest interest to the biological sd-
^32 Rodiopharmoceuticols
cnccs arc perhaps two sj'stems of units One
of these is used to indicate the amount or the
quantity of radioactivitj sshich is represented
b) a p\xn sample, and the other sj'stem is
uiilucd to define the dose uhich a gi\"cn
amount of radioactisitj dciners to the s)'5tem
of interest This system of interest may take
the form of air, tissue or any material of in-
terest, depending on the units one uses to
delineate the dose
Quantity Units
The Curie. It is possible to indicate the
amount of radioactive matenal present m a
given sample as a function of the mass of the
radionuclide present In fact, for m.my years
this was the means utilized to define the
amount of radioactivity present The amount
of radon in cquilibnum with 1 Cm of radium
was adopted as one Cune of activity
Usually, we are not concerned as much
with the mass of the radioisotope as with the
rate of radioactive decay of the radionuclide
Therefore, the Curie unit was defined more
precisely as that amount of any radioactive
matenal which is decaying at the rate of
3 700 X fO'® disintegrating atoms pec sec-
ond In medicine, sub-units of the Cune are
more frequently used, such as the miUicune
(3 7 X 10^ disintegrating atoms per second)
and the microcune (3 7 X 10* dismtcgraiiog
atoms per second)
Specific Activity. Another unit of activity
or quantity which is frequently encountered
IS known as specific activity This term may
be defined as the amount of radioactivity con-
tained m 1 Cm of a substance However,
some sort of qualifying statement must be
made if one is dealing with a compound
rather than an element, m order to avoid con-
fusion Tor csamplc, if the radioisotope
sodium"* 1 $ present in sodium carbonate
(Na’'COj), and one stales merely that the
specific activity is 40 millicuries per Cm , it
IS not known whether the miss indicated is
for sodium carbonate or for sodium only
Therefore, it is less confusing if one speaks
of specific activity (compound), specidc ac-
tivity (element) or specific activity (isotope)
Dose Units
The estimation of the dose delivered to or,
at tim«, absorbed liy a matenal of Interest
IS an caircmely complex task, and the result
B, at best, only a good estimate when com-
pared with the results of other more accu-
rate and precise methods of dose deter-
mination used m nonndioactivc medicinal
products Further complicating the measure-
ment IS the fact that, with certain radioactive
maienals, the dose can be administered to the
body even though the material is located out-
side and at some distance from the body
This of course, is the case with a gamma-
cmitting radionuclide Thus, it is necessary
to consider both external and internal dose,
due to both electromagnetic and particulate
radiations, in order to cover the general topic
of radiation dosage adequately A thorough
understanding of the various units used to
assess dosage is absolutely necessary if one
IS to comprehend the meaning of these terms
The units most frequently used to indicate
the magnitude of radiation dose arc the roent-
gen, the radiation absorbed dose, and the
roentgen equivalent man
The roentgen (abbreviated r ), is the fun-
damental unit of radiation dosage from which
all other units arc derived As it was ongi-
nallv defined at the Stockholm Congress of
Radiology in 1928, it was applicable only
to x-ray dose However, the Chicago Con-
gress of Radiology (1937) modified this defi-
nition to Its present form so that it can be
used for cither x ray or gamma-ray dose esti-
mation Thus the roentgen is defined as the
quantity of x-radiaiion or gamma-radiation
such that the associated corpuscular emission
per 0(X)]293 Gm of air produces m air
ions cany mg one electrostatic unit of quantity
of electricity of either sign This definition
was given international standing by the In-
ternational Commission on Radiological
Units and Measurements (ICRU) m
1956” and again in 1959** Its use is valid
m the calculation of doses from x rays or
gamma rays of quantum energies not ex-
ceeding 3 Mev **
Hic radiation absorbed dose, usually WTit-
ten rad. is the next unit to be considered It
may be defined as that dose of ionizing radia-
tion which results in an absorption of 100
ergs per Gm of any material Tlic rad is the
more recently derived unit which replaced
the older roentgen equivalent physical, or
rep The basic difference between the two is
Radiofion Protection
533
Table 101 Relative Biological Effectiveness and Type of Radiation*
Radution
Biological Effect
RBE
X-rays, y-rays and electrons and /? rays of
Whole body irradiation (blood
all energies
forming organs cntical)
10
Fast neutrons and protons up to 10 Mev
Wiole-body irradiation (cataract
formation critical)
10
Naturally occurring n-particles
Carcinogenesis
lot
Heavy recoil nuclei
Cataract formation
20
• International Commission on Radiological Protecuoo, BnL J Radiol Supp 6, 1955
t If direct comparison with body burden of 0 I pc of radium is not possible
that the rep specifies tissue as the matenal
in which the radiation dose is absorbed, while
the rad may be used for any matenal of in-
terest In contradistinction to the roentgen,
which IS an exposure dose unit used only for
electromagnetic radiations, the rad is a unit
of absorbed dose which may be used for
any type of electiomagneUc or particulate
ra^ation
The roentgen equivalent man, or rem. is
the umt used to express human biological
doses as a result of exposure to one or several
types of lomzmg radiation ** The rem is re-
lated to the rad by a factor which is used to
compare the biologic effectiveness of ab-
sorbed radiation dose due to different types
of radiation This factor is the Relative Bio-
logical Effectiveness (abbreviated R B E ),
and the relationship is
rem = rad X R B E
Unlike the roentgen or the rad, the icm
cannot be measured directly with an instru-
ment It IS determined by correlation of the
biologic effect under observation with a dose
measured by some physical method * There
are at least two determinants of R B E , these
are the biologic effect under observation and
the type of radiation which produces this ob-
servable effect during the penod of observa
tion An estimated relationship between
R B E and tjpe of radiation is presented in
Table 101
RADIATION PROTECTION
From the standpoint of the practicmg
radiophannacist, there can be no more im-
portant facet of his daily practice, for radia-
oon protection concerns not only the safety
of his patients but his owi secunty as well
Anyone who works with radioactive mate-
rials must have a fundamental knowledge of
radiation protection and radiological health
precepts if he is to fulfill his responsibility m
this important area However, m a discussion
of so broad and complex a subject as radia-
tion safety, comprehensiveness must be sacn-
ficed to some extent m the interests of brevity
Therefore, we will confine out discussion to
those aspects of radiation protection and
radiological health which are of concern to
the occupationally exposed individual (as op-
posed to the genera] population) who, m the
course of his daily practice, works with radio-
active materials which are either pure beta or
mixed beta-gamma emitters We thus have
ruled out consideration o! machine-generated
radiation (from x-ray machines, for example)
as well as nuclear reactors and alpha emitters,
in order to shorten our discussion
This compromise or limitation is not as
senous as it may seem There would seldom
be a situation in which a radiophannacist
would be called on to serve as the one who
IS responsible for the over-all safety program,
as It relates to radiation, m his institution
Generally, this penon — usually called the
Radiation Safety Officer — is chosen because
of his strong background in radiation physics,
or, in some cases, he may be a physician who
is knowledgeable in such areas as nuclear
physics, radiation hazards evaluation and
radfodiemistiy In any case, jt is seldom a
good policy to assign radiation safety re-
sponsibilities to one who customarily uses
radioactive matenals m his daily work, just
as it would be unwise to allow the production
department of a pharmaceutical manufac
turer to carry cut the quality control pro-
cedures on the products which this same de-
partment formulates The radiophannacist
has no real need to know every facet of the
53i Rodiophomoceufmh
extremely spccialaed practice of radiation
safet)— or health ph^-sics, as it is often called
Hi$ need is to comprehend enough to allow
him to perform his function m a manner
«hich IS compatible with the safety of his
patients, his environment and himself In the
final analysis, it matters little to whom the
overall rcsponsibilnj is pven, for it is the
direct and inescapable obligation of all who
work, or arc m any way associated, with
radioactive matenah to do so m the safest
possible manner for all concerned The real
problem ss so induce personnel to accept this
responsibility
Maximum Permissible Exposure
In the absence of any definitive evidence
that there is a tolerance level below which
no possible harm can evolve from radiation
dose of such magnitude, reason dictates that
exposure levels be kept at the lowest possible
level which will permit a given procedure to
be accomplished Tunher, the physician, m
determining whether or not to use a radio-
active matcnal m a patient, must weigh the
^siblc harm to the patient against the bene-
fits to be derived from the administration of
the radiopharmaceutical product In any
case, except m cases of therapeutic dosage.
It IS prudent to keep patient exposures below
the maximum permissible levels for occupa-
tionally exposed personnel, and the radio-
pharmacist must develop a method which
Will permit him to complete the task within
these limits
Maximum permissible exposures for oc-
cupationally exposed individuals m the
United States arc Tecommended by the Na-
tional Committee on Radiation Protection
(N C R P )'* These exposure levels arc cate-
gorized and reproduced in part below •
A fjiternal exposure to critical organi
11 hole body head and trunk active blood
forming organs eyes or gonads The maximum
permiwiUc dose (MPD) to the most critical
organs accumulated at any age, shall not exceed
5 rems multiplied by the number of years the
worker is be>ond age IS. and the dose in any
consecutive 13 weeks shall not exceed 3 rems
The accumulated maximum permissible dose
• Maximum Pemimible Body Burdens and
Maximum pem ssible Concentrations in Air and
In Water for Occupational Exposure Handbook 69,
National Bureau of Standards U S. Department
of Commerce. Washington, DC. 1939
may be calculated from the relationship
MPD = (N — 18) X 5 rems, where N u the
age m years and is greater than 18 In arriving
at these values it is assumed that one will not
have occupational exposure to radiation prior
to age 18 The maximum permissible weekly
dose that is used most frequently remains at
300 millirems, but exposures of this magnitude
each week of the year obviously would be In
excess of the recommended value
B External exposure to other organs Skin
of whole body MPD = 10{N — 18) rems, and
the dose m any 13 consecutive weeks shall not
exceed 6 rems This rule applies to radiation of
low penetrating power Hands and forearms,
feet and ankles MPD = 75 rems per year, and
(he dose m any 13 consecutive weeks shall not
exceed 25 rems
C. Internal Exposures The permissible levels
from internal emitters shall be consistent as far
as possible with the age-proration and the dose
principles given in Jhe preceding paragraphs
Control of the internal dose is achieved by
limiting the body burden of radioisotopes This
IS generally accomplished by control of the
awrage concentration of radioactive matenals
in the air, the water or the food taken into the
body Since it would be impractical to set dif-
ferent maximum permissible concentration
(MPC) values for air, water and food for radi-
ation workers as a function of age, the MPC
values are selected in such a manner that they
conform to the established limits when applied
to the most restrictive case In other words, they
are applicable to radiation workers of any age,
assuming that there is no occupational exposure
to radiation permitted at age less than 18
The maximum pcrmissibic average concen
tratioRS of radionuclides in air and water are
determined from biologic data when such data
are available, or they are calculated on the basis
of an averaged annual dose of 15 rems for most
individual organs of the body, 30 rems when
the critical organ is the thyroid or the skin, and
5 rems when the gonads or the whole body Is
the cntical organ For bone sccken (radio-
nuclides which tend to accumulate in bony tis-
sues), the maximum permissible limit is based
on the distribution of the deposit the Relative
Biological Effectiveness and comparison of the
energy release in the bone with the energy re-
lease delivered by a maximum permissible body
burden of 0 1 meg Ra~* plus daughters A
comprehensive listing of maximum permissible
body burdens and maximum permissible con
centrations of radionuclides in air and water for
ocoipational exposure, in which body organs
of reference are tabulated may be found In the
I C.R P. Internal Radiation Report®*
Radiation Protection 535
Methods of Protection
The means of protecting oneself from the
harmful effects of ionizing radiation must be
considered from the standpomts of those
radiations that present a hazard even when
they remam outside the body and those which
are likely to be harmful only when the radio-
nuchde is m the body
There are, basically, only three rules to
keep in mmd when working with externally
hazardous radioisotopes Ihese are expressed
m terms of tune, distance and shieldmg That
is to say, make exposure to a source of ioniz-
ing radiation as bnef as possible, mcrease as
much as possible one’s distance from the
source, and make use of suitable absorbers
or shields to dimmish to a reasonable level
the amount of radiation reaching the body
It IS frequently necessary to make use of ^
three of these methods
Insofar as the radiopharmacist is con-
cerned, radionuchdes wLch are considered
to be hazardous externally arc those which
emit gamma rays, as well as certam beta-
emitting radioisotopes of relatively high
energy The dose rate from a pomt source*
of 8 gamma-ermtter varies mversely with the
square of the distance from that source
This relationship may be expressed mathe-
matically by equation ( 1 )
h (R:)=
( 1 )
where Ii is the gamma mtensity at distance
Rt from the source and I<i is the ^imma m-
tensity at distance Ri For example, it is
known that the dose rate from a I-milltcune
pomt source of Na^^ at a distance of 1 cm
IS 18 4 r per hour If one wished to find the
dose rate at a distance of 10 centimeters, the
answer may be conveniently calculated from
the equation (2) :
18 4 _ (10)g
h “■ (D*
and I 2 IS found to equal 184 miUiroentgens
per hour It should be emphasized aeam that
the mverse square law is valid only lor point
sources with no shieldmg or attenuauon am-
siderations, it does not apply to radiation
* A point source u a source which is smali in
physical dimeosians when compared with the
tance from the detector
fields due to multiple sources, beams of radi-
ation or to extended sources Howwer, the
law IS approximately correct as long as the
distance from the detector or pomt of mter-
est IS at least three times the physical dimen-
sions of the source
Beta-cimttmg isotopes of relatively high
energy may constitute an external hazard in
two situations If the radionuclide comes mto
physical contact with the skm or the eyes
and IS not removed immediately, a radiation
bum may result Secondly, beta-ermtters may
release x-rays when the beta particles impinge
on and are stopped by certam materials
These x rays are known as Bremsstrahlung
or ‘ brakmg” radiations The amount and the
character of these x rays are functions of the
kinetic energy of the particle and the atomic
number of the absorber This phenomenon is
analogous to that which exists m an x-ray
lube, m which electrons are accelerated across
a large difference m potential to impmge on
a target of high atomic number, such as
tungsten Bremsstrahlung is an important
consideration m working with radionuclides
such as phosphorus *2 plastic formulations of
low atomic number are frequently used to
shield synnges m which relatively large doses
of P” are to be admmistered and a thm sheet
of lead IS added to the synnge holder to shield
against the electromagnetic radiation which
IS produced (Fig 209)
lulenial Hazards Protection against radio-
nucbdes which are hazardous only if they
gam entrance to the body is generally afforded
by good laboratoiy pioceduie and
personal hygiene Many sets of rules for con-
duct m radioisotope laboratories have been
advanced by radioisotope workers, all of
which are mtended to reduce to a nunimum
the hazard of isotope work A representative
set of rules appears m the Radiation Safety
Guide m current use at the National Insti-
tutes of Health** and is quoted m part below
Each individual at the NIH who has any con-
tact with radioactive materials is responsible
for
1 Keeping his exposure to radiation as low
as possible, and specifically below the Maximum
Permissible Exposure as listed in Appendix
Table 1 Laboratory air and water concentra
lions shall be maintained below the levels in
Appendix Table 2
2 Weanng the prescribed monitoring equip-
536 Rodtophormaeeulicols
riQ 209 Radioisotope synnge with plastic and lead shields (National Institutes of Health,
U,SPH5)
ment, such as film badges and pocket dosim*
eters, in radiation areas
3 Sur\e)ing his hands, shoes and body for
radioactivity, and removing all loose contamina-
tion before leaving the laboratory to smoke, eat.
etc
4 Utilizing all appropriate protectise meas-
ures such as
(a) Wcanng protective clothing whenever
contamination is possible, and not wearing
such clothing outside the (aboratory area
(b) Wcanng gloves and respiratory pro-
tection w here neecssar)
(c) Using pipette filling devices NEVER
PIPETTE RADIOACTIVE SOLimONS
DV MOUTH
(d) Performing radioactive work within
confines of an exhaust hood or glove box
unless serious consideration has indicated
the safety of working in the open
5 Avoiding smoking or eating in labora-
lones Smoking or eating may be permuted Jo
an office area of the laboratory that has been
demonstrated to be free of contamination. Re-
fngeraton will not be used jointly for foods
and ndioactiv e materials
6 Maintaining good personal hygiene
(a) Keep fingernails short and clean.
(b) Do not 'work with radioactive ma-
terials if there » a break m the skin below
thewnst
(c) Wash hands and arms thoroughly be-
fore handling any object which goes into Ihc
mouth, nose or eyes
7 Checking the immediate areas, c g , hoods,
benches, etc . in which radioactive materials arc
being used at least once daily for contamination
Any contamination observed should be removed
immediately
8 Keeping the laboratory neat and clean
The work area should be free from equipment
and matcnals not required for the immediate
procedure Keep or transport materials m such
a manner as to prevent breakage or spillage
(double containcn), and to ensure adequate
shielding Wherever practical, keep work sur-
faces covered with absorbent material, pref-
erably m a stamless steel tray or pan, to limit
and collect spillage in case of an acetdenL
9 Labeling and Isolating radioactive waste
and equipment, such as glassware, used in
laboratories for radioactive materials Once used
for radioactive substances equipment shall not
be used for other work, or sent from the area to
cleamng facilities or repair shops until demon-
strated to be free of contamination
10 Requesting Radiation Safety Office super-
vuion of any emergency repair of contaminated
Radiahon Profedion
537
equipmeot m the laboratory by shop personnel
At no time shall service personnel be permitted
to work on equipment in radiation areas with
out the presence of a member of the laboratory
staff to provide specific mformation
11 Reporting accidental inhalatton, mges
tion or injury involving radioactive materials
to his supervisor and the Radiation Safety
Office and carrying out their recommended cor
rcctive measure TTie individual shall cooperate
m any and all attempts to evaluate his exposure
12 Carrying out decontamination procedures
when necessary, and for taking the necessary
steps to prevent the spread of contamination to
other areas •
The extremes to which one must go to pro-
tect oneself from a source of ra^oactivity
depend on many things Among things to be
considered are the quantity of radioactivity
with which one is to work, the type and the
energy of the radiation emitted by the source,
the complexity of the radiopharmaceutical
procedure with which one ts faced, the physi-
cal and the biological half lives of the com
pound, and the physiologic behavior of the
compound, should it gam entrance to the
body However, it is unportant to understand
that all radioactive contaminants — regardless
of their type of emission — may be hazardous
if they gam entrance to the body, they differ
only m the degree of that hazard
^eoiical Radioprotective Agents. While,
m the author’s experience, the use of chem-
ical radioprotective agents has never been
indicated m the practice of radiopharmacy,
some mention of these compounds should be
made m any discussion of radiation protec-
tion Presumably, these compounds might be
used when the probabihty exists of receiving
a single, relatively large ^se of radiation Jo
general, these compounds must be adminis-
tered pnor to or during the penod of irradi-
ation, no beneficial effect is to be expected
from administration of these compounds after
exposure
Smee radiauon damage to biologic tissue
probably results from the ionization of cer-
tain tissue constituents and, m certam cases,
the production of free radicals, a number of
mechanisms of action of protective agents
may be suggested. These chemical com-
• Brown J M , and Cool, W S. National In
slitules of Health Radiation Safety Guide Wash
ington. Government Printing Office 1959
pounds may react directly with the ions and
the free radicals to neutralize or reduce their
toxic effects, they may exert some purely
physical shielding effect to protect against the
products of ionization, or they may reduce
the o^gen tension ra the tissue environment
to dunmish the production of strong oxidiz-
ing agents resultmg from the reaction of the
ions and the free radicals with oxygen
Early work of Patt and his associates at
Argonne National Laboratory mdicated that
the pnor ingestion or injection of compounds
containing a sulfhydryl group, such as cer-
tam ammo acids, significantly reduced the
number of deaths m animals that were given
lethal doses of radiation Through a sys-
tematic approach to the problem, Doherty
and his co workers at Oak Ridge National
Laboratory discovered a modified ammo acid
configuration which showed great promise m
Its protective effect on laboratory animals
This substance is S-(2 ammoethyl)isothiu-
romum bromide hydiobromide, commonly
called AET, which breaks down m the body
to the compound 2 mercaptoetbylguanidme
hydrobromide (MEG) , it is the latter com-
pound which exerts the protective effect **
While, on theoretical grounds, these com-
pounds should be effective m preventmg acute
radiation sickness in patients receivmg large
therapy doses of radiation, the results thus
far have been far from uniformly successful
However, the search goes on m many labo-
ratories throughout the world
Acceptable Risk
It may seem quite logical to question the
wisdom of engagmg m radiopharmaceutical
practice m view of the possible hazards of
radiation exposure In fact why should not
one avoid all exposure to radiation? The fun-
damental impracticality of this proposition
IS apparent when one considers that man has
been bathed m a field of radiation since time
immemorial — an exposure over which he has,
at best, only a limited control This is, of
course, the natural background radiation
from the cosmic rays and from certam natu-
rally-occumng radionuclides which are
widely dispersed throughout our environment
(and, mdeed, throughout our body as well)
It has been estimated'’* that the total amount
of external background radiation to which a
53B Ra<nopharmaceulicals
Ffo 210 Portable Geiger Kfueller aur
\ey meter (National Institutes of Health,
PJI5 )
kmizing radiation With respect to the types
of compulations usually encountered m the
use of radiopharmaceutical products, these
equations may be categorized as beta dosim
eiiy, gamma dosimetry and beta plus gamma
dosimetry equations
Deta Dosimetry Equation (3) is used to
compute the beta dose m rads (D^) for com-
plete disintegration of the radionuclide (oo)*
DjCm) =73 8E^CoT'*Ce(t) (3)
uherc is the mera^e beta particle cneigy
in Mev, Co IS the mitial concentration of the
radionuclide in /ic/Gm of tissue, and
T*(cfT ) is the effective half life Effective
half life IS defined as the time required for
a radionuclide fixed m tissues to be dimm-
ishcd by a factor of SO per cent, due to the
combined effects of radioactive decay and
biological elimination Effective half life may
bccomputcd from equation (4)
T«(eff ) =
Diologtcal half life X Radioactive half life
Diological half life -f- Radioactive half life
(4)
man is subjeaed every day of his life is of
the order of 0 3 mr per day, intemally, there
arc at least three naturally-occurring radio-
isotopes svhich administer to a man weighing
70 Kg a radiation dose equivalent to ap-
proximately 0 1 mr per day These radio-
nuclides arc potassium”, carbon^* and
radium***
Consideration of radiation exposure m
this context leads Inevitably to the concept
of 'acceptable nsk ” This has been defined*
os a ruk that ts made so small that it a readily
acceptable to the average individual, that is,
the risk is essentially the same as that present
In ordinary occupations not involving expo-
sure to radiation The concept of acceptable
risk obviously implies that those who work
with radionuclides have had sufficient train-
ing and experience to allow them to do so
safely Most authontics today arc in agree-
ment concerning the validity of this concept
CALCULATIONS
There are a number of equations which
ore basic to the calculation of dosage from
It should be emphasized again that tables
of beta energies found in the literature are
tables of maximum beta energies for a given
radionuclide The average beta energy used
m most calculations is approximately VS the
maximum listed in the reference tables
To determine the beta dose m rads for any
time (t) after the administration of a given
radioisotope when i is m days, equation (5)
KUSed
D, = E^CoP* (eff ) ( 1 - e-* <»« > )
(5)
Gamma Dosimetry. There are a number of
reasons why gamma ray dosimetry is not as
simple a procedure as beta particle dosimetiy
In the case of beta particles, although it may
not be apparent, an assumption ts made that
the cnei^ dissipated per gram of tissue ts
the same as the energy absorbed in the same
mass of tissue Because of the much longer
range and an infmitely greater ability of a
gamma ray to penetrate matenals, no such
assumption may be made in this case The
dose delivered by a gamma emiilcr depends
on a number of parameters, such as the effec*
Radiotton Detection Instruments 539
Fio 211 Portable ionization chamber survey meter (Cutie Pie) (National Institutes of
Health.USPHS)
tive half life of the radionuclide, its concen-
tration m the tissue and, also, to a large
extent, the energy of the gamma ray A rela-
tionship which IS frequently used to deter-
mine the gamma dose m roentgens for com-
plete dismtegration of the isotope («o) is
given by equation (6)
Dr (e») = 0 0346rp|CoT«(eff ) (6)
where
p = Density of tissue m Gm /cm *
r = Emission constant (r/mc/hr
at 1 cm.)
g = geometry factor, which is a
function of size and shape of the tissue
volume and the penetration of the radiation
(tables available)
Co = initial concentration of the
isotope m pc / gram of tissue
T^^CeS ) = effective half-life of the
isotope in days
If one wishes to know the gamma dose for
any tune (t) when t is m days, equation (7)
may be used
RADIATION DETECTION
INSTRUMENTS
Since human sensory perception is m-
capable of detecung either the presence or the
magnitude of a radiation field, mstruments
have been developed to make these deter-
mmations It is customary to classify radia-
tion detection instruments accordmg to the
use to which they are put or with respect to
the type of medium m which the determina-
tion IS made ^Vhen categorized accordmg to
use or function, they may be classified as sur-
vey instruments, personnel monitoring instru-
ments and laboratory mstruments
Survey Instruments
Survey instruments are usually portable,
relatively simple m design, and may display
a readmg m roentgen units or counts per
umt time They are used for gross determma-
uons of the presence and the magmtude of a
radioactive source or contammation Two of
the most frequently used survey instruments
are the portable Geiger counter (Fig 210)
and the ionization chamber instrument (Fig
D^ (t) = 0 034^00*^(62 )(1 —
(7)
540 Rodiopharmaceultcals
Fio 212 Film badgci standard and wnst. (National Institute of Health U5 P )
211) (often referred to as a ‘CmicPic”
(abbreviated QT-) m the literature)
PCRSO'tNCL MoMTOWSG IsSTRUMtNTS
The function of instruments in this cate*
gory IS to afford a reasonably reliable esti-
mate of the radiation dose uhich an occupa-
tionallj exposed individual rcccises m his
daily work Since these devices arc concerned
with the health and the welfare of radiation
\JS PH5)
workers and, thus, may serve a legal function
should a claim for radiation injury anse, they
arc among the most important of all radia-
tion dctccuon mstruments to both the worker
and management However, unless they are
of good qualii) and arc used properly in a
well founded health phj'sics program, the re-
sults may be something less than satisfactory
Two of the most important personnel
monitonng devices arc the film badge (Jig
212) and the pocket dosimeter (Jig 213)
A film badge i$ an opaque packet containing
a photographic film whicli vanes in known
scnsitivit) to radiation of diverse energies
and types After exposure to radiation, it
will be found, on developing, that a darken-
ing of the film has occurred as a result of the
interaction of the incident radiation particles
or ra}s with the silver halide granules m the
tTwJft’/aw TVit tA -ityX-
enmg of the films, as determined by measur-
ing the transmittance of light through the
film on a densitometer, gives a fair!) accu-
rate indication of the amount of radiation
striking (and reacting with) the badge In
order to make this determination, standard
or “comrol" films from the same emulsion
number as the batch worn by workers arc
exposed to known amounts of radiation of
various t)pes and energies The control films
arc then developed at the same time as the
‘ unknown” films, or those actually worn by
the radiation workers, using the same dc-
VTloping technics and chemicals The densi-
Radiation Detection Instruments 541
Fig 214 Regions of loitnunent response (From Cbase, G D Principles of Radioisotope
Methodology, Minneapolis Burgess)
tometer readings from the control films versus
the dose administered are plotted on graph
paper, and then the e;tposure of the unlmown
films may be read from the graph WbQe this
procedure seems simple and forthright, it
must be emphasized that an exceptionally fine
system of quality control on the part of the
group providing the film badge service and a
sincere, conscientious attitude in the radia-
tion worker who wears the badge are neces-
sary if results are to be meaningful Neither a
haphazard calibration procedure nor a film
badge which should be worn on the person
of the worker but which is placed, soon to be
forgotten, in his desk drawer wll provide
significant records of radiation exposure
Pocket dosimeters, or pocket ionization
chambers, resemble fountain pens m outward
appearance In actuality, these instruments
are self-contained electrometers in which the
amount of ionization m a sensitive volume of
gas within the electrometer is measured This
ionization then can be related to the amount
of radiation which has reacted with the elec-
trometer Both the film badge and the pocket
dosimeter indicate a cumulative dose of
radiation, rather than a dose rate
Laboratory Instruments
These are the most sensitive of all radia
tion detection devices This kind of instru-
ment IS employed when an assay or calibra-
tion of a source of radioactivi^ is necessary
The conditions under which these instruments
are used lend themselves well to reproduci-
bility of results, a factor which is seldom, if
ever, attainable wth other types of mstni
ments or devices
It IS obviously impracticable to discuss or
even list the considerable number of labora-
tory instruments currently available in the
United States However, it may be con-
venient to classify such devices m terms of
the detector utilized m the particular sys-
tem- Those m general use include ionization
chambers, proportional counters, Geiger-
Mueller counters and scintillation counters
The first three types are known as gas filled
detectors (although, m certam instances, the
“gas” IS merely the atmosphere around us)
and include some of the oldest — yet most
widely used — radiation detectors devised
Scmtillation detectors, while relatively new,
are extremely valuable and, perhaps, the most
versatile of all
542 Rodlopharmaceuticols
Ionization Chamber Detectors. BasicaQy a
detector of this l)pe is designed to measure
quantity of ionizing radiation m terms of
the charge of elcctncit) associated svitb Ions
produced within a defined solurac” Thus,
In the strictest sense, Geiger Mueller counten
and proportional counters should also be
included w this group However, it is
customary to qualify this definition by con-
sidering detectors as ionization chambers
only if there is no gas amplification factor
mTOlvcd If one plots the number of ions
collected ^rsus the applied \oltage, five
regions of instrument rcs^nse will be noted
as the soltage applied is increased abos'C
zero (Fig 214) In the first region, known
as the region of recombination, the ions
which are formed are under so low a voltage
gradient that they tend to recombine with
each other rather than migrate to the elec-
trodes and be collected. As the wltage is
increased, this recombination phenomenon
decreases and actually disappears at the start
of the second region It is obvious that radia-
tion detection instruments cannot be oper-
ated m this region
TTie second region is know-n as the ioniza-
tion region and represents a point at which
all of the ions formed are collected The
electron portion of the primary ion pair which
IS formed is accelerated toward the anode of
the chamber, while the positive ion moves
no 215 Gas flow tJelcctof for
solid beta-emitting samples (may
be used as & window less or an ultra
thin window detector) (Nuclear
Chicago Corp )
somewhat more slowly toward the cathode
At some large voltage increment above the
region of recombination, there is a saturation
point at which all of the ions formed are col-
lected This IS known as the saturation cur-
rent region or ionization chamber region
An excellent example of an ionization cham-
ber instrument is the Launtsen electroscope,
which IS widely used in the measurement of
gamma radiation Another ionization cham-
ber instrument which has been used to meas-
ure beta and gamma radiation is the Lands-
verfc electrometer
If one applies sliJl higher voltage to the
detector, the number of ions collected will
also increase This apparent ambiguity (more
ions being collected than arc formed by the
primary radiation source) is due to the in-
creased force with which the electrons are
accelerated toward the anode With a suffi-
ciently high voltage — and resultant velocity —
these migraung electrons produce a second-
ary ionization of the gas in the detector, re-
sulting m an amplification of thepnmary ion
current produced by tlie radiation As the
applied voltage increases, the gas amplifica-
tion factor also inacascs Since the size of
the current pulse which results is propor-
tional to the applied voltage and to the
number of primary ions formed, this region
IS known os the proportional region It should
be noted that the number of pnmary ion pairs
formed is a funcUon of the specffic Ioniza-
tion of the radiation Thus, an alpha particle,
with Its relatively high specific lonizauon,
will produce a larger current pulse than will a
beta particle, of a correspondingly lower
specific ionization Proportional counters arc
extremely venatile in that it is possible to
distinguish between alpha and Mta gamma
radiations
If the vxiltagc is increased still further,
gas amplification is also increased, this is
due to an even greater acceleration of elec-
trons than that observed m the proportional
region In this, the fourth region of instrument
response (known as the Geiger Mueller
region), a veritable avalanche of ions is pro-
duced and gas amplification factors as high
as 10’* arc not uncommon Over a relatively
narrow range known as the operating plateau,
the count rate produced by this avalanche of
Ions H nearly independent of applied voltage
lAo OACT viTY emcroi camua srccrtoMnEi
Fio 2!6 Block diagram of gamma ray spectrometer (National Institutes of Health,
U^PJIS)
m a good detector That is to say, small devised method of detection which is in wide
changes m either Ime voltage or applied volt- use is Chat of scmtOJation Systems employ-
age will have a relatively small effect on mg this detection medium may be of either
count rate The mstrument also is relatively the solid ciystal or the liquid type Both types
independent of the specific ionization of the have been used successfully to detect and
tnggermg particle or photon within this measure alpha, beta and gamma radiations
plateau The Geiger Mueller region is sensi- Whatever the detection medium, whether
tive to any radiation event which produces sohd or liquid m nature, the basic pnnciple
even a smgle ion pair, which means that in is similar When radiation, of either electro-
dividual lonizmg events may be detected An magnetic or particulate nature, mteracts with
obvious example of an instrument which a detector of suitable material, photons, or
operates withui this region is the Geiger- quanta of visible light, are emitted by the
Mueller counter, which is one of the oldest molecules of the detector These light pulses
of all radiation detection instruments These are then observed, multiplied and amplified
detection devices may be of the older “end by a photomultiplier tube and, finally, after
window” ty-pe, m which the gas is enclosed additional amplification, counted by an elec-
withm a Geiger tube which the ionizing radia- tronic adding machine known as a scaler The
Uon must penetrate to be detected, or of the process is essentially one m which the energy
more recent variety of windowless Sow of the radioactive material is transformed
Geiger counter (Fig 215) In the latter case, into visible hght energy m the detector and
the radioactive source is literally bathed m mto electrical energy m the photomultiplier
the detecting gas, resulting in a much ht^er tube It is this electrical energy which ulti-
detection efficiency In the past, Geiger- mately is counted m some suitable device
Mueller counters were widely used to detect Solid Detectors If one utdizes the
both beta and gamma radiation There are proper solid crystal, it is possible to detect
now much more efficient detectors for use alpha, beta or gamma radiation However, in
with gamma emitters, so that beta counting this section we shall consider only those solid
is the most frequent function of a laboratory detectors which are used to measure gamma
mstrument of this type radiation In most cases, a thallium activated
The fifth region of mstrument response is sodium iodide crystal is used as the phosphor
attained when the applied voltage is increased A block diagram of such a countmg system is
beyond the Geiger Mueller region Like the shown (Fig 216) When gamma rays im-
first region (thatof recombmation), this level pmge on the crystal detector, the mtensity of
is not utilized m radiation detection instru- the resultant scmtillation is substantially pro-
ments, for, m this instance, the gas arcs and a potuonal to the energy of the gamma radia-
state of continuous discharge results This is tion The number of pulses which are caused
the region of continuous discharge in the crystal by the unpmging radiation is a
SemtiUaUon Detectors. The most recently measure of the dismtegration rate of the
5i4 Rodlopharmaceulieoh
no. 217. Camnu rav spnlrometer with »cintilb(ion ucll detector. (National Imtitutcs of
Health. U.S P.H.S.)
sample, when compared with a known stand- phoioclectrons arc accelerated by the dillcr-
ard of the same radio3Cti\-c species. The ence in potential applied to the tube. The
amplification factor in a photomultiplier tube photoclcctrons, in this acceleration through
w cependent on the number of stages In the the tube, strike a succession of other surfaces,
tube; as light pulses from the crystal cause or stages, known as djTiodcs, with secondary
the emission of photoclcctrons from the light- emission of electrons occurring at each sur-
semitive phoiocaihode within the tube, these face. For each incident electron hitting one of
Fio 218 Three channel hquid scmtiUation spectrometer and freezer (Nuclear-Chtcago
Corp)
the dynodes, there are approximately four
secondary electrons emitted Thus, ampU-
fication factors lo good photomultiplier tubes
are of the order of 10® to 10^® The pulse
leaving the photomultiplier is given additional
amplification and then fed into the spectrom
eter, or pulse height analyzer Usmg the dis
cnmmation mherent m the spectrometer, the
instrument can be adjusted to a given dts
Crete energy of a particular gamma-emittmg
radionuclide, and only the pulses caused by
impmgmg radiation of that energy will be
counted This technic, knosvn as counting
on the peak,” is utilized when other radio
active materials m the vicinity of the detector
may give false count rates or, in other cases,
when the daughter, or decay product, of the
radionuclide of interest is also a gamma
emitting isotope Figure 217 Dlustrates a typi
cal gamma scmtiUation spectrometer
Liquid Detectors Within the last dec-
ade, there has appeared on the American
commercial market a system m which beta-
emitting isotopes, particularly those of low
energy such as C^* and H*, may be counted
with a fair degree of efficiency This sj'stem
(also n scintillation method) is known as
liquid scmtiUation countmg and, as the name
implies, the detection medium m this case is
liquid in nature Hiere is an intrinsic ad
vantage m this method of detection, for the
sample coatammg the radioactive matenal is
usuaUy dissolved m the detectmg medium,
thus placmg the atoms of the radionuclide m
mtunate contact with those of the detector
In so doing essentially 100 per cent geometry
IS obtained, and self absorption is kept to
a minim um.
While there are certam similanlies between
solid and liquid scmtiUation counters, there
are certain important differences also Ihese
differences are largely due to three factors
(1) beta energies under observation are
usnaUy of much lower magnitude than the
Fio 219 Remote pipetting iloiec for bulk £ainina-«milting rai]joiM>to{>es (National Insti
tuta of Health, P )
gamma energies previously considered, (2) ponents m the system The operation of the
the cHiciency of liquid santillalors m enuttmg photomuUipIien and the detector at reduced
light ts much less than that of solid crystals, temperatures m a freezer greatly dimmishes
and (3) all photomultiplier tubes produce a the rate of thermal pulses occurring m the
considerable and s-anablc number of thermal photomultiplier (Fig 218)
pulses The amplitude of these thermal pulses To limit the acceptance of the remaining
1 $ quite similar to the amplitude of the beta thermal pulses by the spectrometer, a co*
decay esents which one wishes to measure incidence arrangement of photomultiplien is
Thus, discrimination against the tbcnnal used Two photomultiplier tubes siew the
pulses w not possible, as was the case m the sample simultaneously, and any scintillation
gamma spearometer, for the instrument is occurrmgm the sample will be “seen” by both
meapab’e of dutmguishing beiw cen Icplimate tubes at essentially the same instant The co-
pulses onpnaimg m the radioactive source tnadence circuit allows such an esent to pass,
and tbcnnal pulses from the photomultiplier but blocks any random event which occurs in
tube, waihoot the presence of additional com- only one photomultiplier Thus, unwanted
Radiation Detection Initruments
547
Fio. 220. Remote pipetting devices for beta*eioittiog and low'sctivity gamma-emittiag radjo*
nuclides. (KaUoaal Institutes o( Health, U.S.P.H.S )
thermal pulses (often termed “accidentals” (3) it must be compatible with solubOity
in the literature) are practically eliminated restrictions imposed by the nature of the
from the background in a good liquid scintfl- counting solution and by the temperature at
lalion counting system. which the counting is performed.'’ Since the
While It is sometimes necessary to count most efficient light emitters have emission
samples in a suspended state (even a thixo- spectra which lit within a very narrow range
tropic gel has been utilized), it is the usual of wavelengths, it is common practice to
practice to dissolve the sample in a suitable employ a combination of two solutes in a
solvent which also contains the phosphor, or pven counting “cocktail” — a primary scintil-
scuiUllator. The liquid scintillator consists lator to provide a large number of photons,
of a solute and a solvent. The solute emits a and a secondary semtiUator to shift the
burst of photons for each radioactive event emission spectrum of these photons to a more
which deposits energy m the solution, and convement wavelength for detection by the
the solvent absorbs energy and transfers it to optics in the system.
the solute. ^ There are many different liquid scintiUa-
For a solute to be useful in liquid scinffi- tion counting solutions used to count a va-
lation counting, at least three criteria mnst be riety of sample types, and the reader is
met: (1) It must be an efficient light emit- directed to other references for a more com-
ter; (2) it must produce a photon spectrum prefaeosive discussion and listing of these
which, in a conwntional scintillation detector, substances.®* A representative example of a
will be efficiently transmitted and reflected in “cocktail” used (and modified) in the au-
the optical system and converted into elec- thor's laboratory for the counting of aqueous
trical energy by the photomultiplier; and samples, and originally described by Bruno
548 Rodiopharmaceuticals
rto 221 Ridiochromitognm scanner, witb couat rate mefcr and rectiltnear recorder
(National Institutes of Health U S P H S }
and Christian is listed below to illustrate
the types of chemical entities which are used
as solutes and solvents m liquid scmtillatioo
counting
Dimethyl POPOP, 1 4 bis 2 (4
methyl 5 phenylosarolyl)
benzene OtOOGm
PPO 2 5*<lipheny1oxazoIe 4 000Gm
Ccllosolvc* (ethylene glycol
monocih)! ether) 5000 ml
Toluene 5000 ml
It is interesting to note that the designations
dimethyl POPOP, PPO, and others arc much
more frequently noted in the literature than
are the chemical names also listed above All
chemicals used m preparing ‘ cocktails’
should be of scmtiHation grade
* Cellosotve* (Carbide and Carbon Chenucab
Company)
OTHER EQUIPMENT
Much of the equipment used in radio-
pharmaceutical practice is quite similar to
that tthich IS utilized ui more lemihar areas
of pharmaceutical practice However, be
cause of the inherent hazard involved in
working with radioactive matenals, there are
a number of somewhat specialized pieces of
equipment which should be mentioned
For example, there arc various remote
pipetting devices in common use m radio-
pharmaceutical laboratories Figure 219
shows an mstrument used to withdraw ali-
quots of a gamma-cmitting radionuclide from
a bulk bottle in such a way as to prevent the
operator from receiving an unnecessary radi-
ation dose during the procedure Note that
the bulk bottle is stored bchmd a barricade
composed of Intcrlocljas lead backs, the
Dosage Forms 549
Fia 222 Radioisotope eloved box, wub aseptic transfer m progress (Kational Institutes
of Health, USPJIS)
mircor faalitates placing the pipette in the
bottle without looking over the lead shielding
When It IS necessary to pipette beta emit-
ters or relatively small amounts of gamma
emitters, two other remote pipettors (Fig
220) may be used to avoid pipettmg by
mouth
Another example of specialized equipment
IS the radiochromatogram scanner (Fig
221) This instrument is frequently used to
establish radiochemical purity m products, it
consists of a mechanism which drives the
paper strip chromatogram on which the sam-
ple has been spotted through the gas flow
detector A rate meter — to integrate the
count rate into aserage counts per mmutc —
and a recorder — to present a wTitten trace of
the count rate — are usually included m this
system
Gloved boxes, or hoods (Fig 222), arc
also frequently used m this specialized area
of practice These enclosures serve to confine
contammation dunng a given procedure and
may have ultraviolet hghts withm them to
provide an aseptic environment for sterfle
procedures Since these boxes should be
maintained at a negative pressure with re-
spect to the laboratory air, m order to pre-
vent the outfloN/ of air borne contarmnaots
a bacterial retentive filter is necessary m the
air intake Ime Customary laboratory utili-
ties, such as air, gas and vacuum, are usually
mcorporated m gloved boxes for the con-
venience of the operator
DOSAGE FORMS
Commercially available radiopharmaceuti-
cals are limited at present to oral dosage
forms and a variety of injectable products
Those in the oral categoiy are supplied as
either an oral solution or capsules The m-
550 Radiophannaceuticals
jcciablc catcgor) ts represented by products
v-hjch may be administered bj the intra-
venous, the intramuscular and the intracavi-
tary routes of injection In certam research
applications, both the topical and the inhala-
tion routes have also been utilized.
FORMULATION AND DISPENSING
PROCEDURES
la gcacra}, fonnuUtioa procedures in the
practice of radiophannacy do not differ
greatly from similar procedures mwlving
nonradioactivc medicaments \vhich base been
discussed m other chapters in the text The
exceptions obviously arc a result of the radi-
ation hazard involved \Vhilc a drop of solu-
tion or a small quantity of powder released
to the environment m the course of a rou-
tine pharmaceutical procedure not mvolving
radioactive matcnals is seldom cause for
alarm, it becomes a problem of major con-
cern in radiopharmaccuucal practice Thus,
strict attention to the avoidance of contami-
nation, if possible, and the discovery of such
contamination when it exists are of para-
mount importance m radiopharmaceuucal
practice
Since many of the materials with which
one deals in this specialty are heat labile, if
sterilization is required, some system of ster-
ile ffltrauon must be used In this regard, one
should remember that the amount of dis-
solved solid which represents the active con
stituent may frequently be a microgram or
less of mass Thus, adsorptn e filtration media
should be avoided wherever possible
If an autoclave is to be used for steriliza-
tion, It is usually wise to incorporate a water
condenser m the steam discharge line to pre-
vent the release of large amounts of poten
tially radioactive vapor into the laboratory
oir should Ical^agc or breakage of a sealed
container undergoing stcnlization occur
The adsorption phenomenon mentioned
previously can also occur m the use of glass-
ware, including that used to package the Onal
product Should this occur, considerably less
radioactive material might be administered
than the labeled potency would imply The
use of certam silicone compounds of a non-
toxic composition to coat the walls of glass-
ware used for radioactive matcnals tends to
minimize this adsorption process Another
method which is used to prevent adsorption
consists of “saturating” the glassware by
soaking it in a earner, or nonradioactivc,
solution of the same composition as that of
the radioactive solution pnor to use with the
radioactive matenal
Proper quality control procedures are ab-
solutely required m the formulation of radio-
pharmaceutical products Always included
are checks on the identity o( the radionuclide.
Its concentration in the ffnal product, the ab-
sence of radioactive contaminants in the final
product and, where parenteral products are
mvolved, a pjrogen and stenhty test ^Vhile,
m a commercially procured radiopharmaceu-
tical product, the manufacturer is responsible
for the quality control on the products sup-
plied by his company, there frequently exists
a need to prepare dosage forms containing
radionuclides extemporaneously at the hos-
pital level In the latter case, the respon-
sibility for quality control rests with the
radiopharmacist who formulates the product.
Paefcagmg In situations where radiophar-
maceutical products are to be shipped from
the supplier to the user, regulations of the
United States Atomic Energy CommissiOQ
(USAEC), the Interstate Commerce Com-
mission (ICC) and the Post Office Depart-
ment are quite specific m the protective
procedures to be followed In addition, if
shipment is to be made by air, regulations
of the Civil Aeronautics Board (CAB) must
be observed, and, if the shipment is to be
made over water. United States Coast Guard
Regulations apply While it may appear that
there IS a vcntaolc host of conflicting mterests
and regulations involved in the shipment of
radioaaive materials, there actually is a sur-
pnsing degree of correlation between them
In general, these regulations limit the dose
rate at the surface of the outside container
of a shipment of radioactive materia! and
impose certain labclmg criteria which must
be followed In addition, when radioactive
liquids arc shipped, there must be sufficient
absorbent material withm the inner package,
in close contact with the container confinuig
the liquid, to completely absorb the total vol-
ume of liquid should rupture of the iimer
container occur The inner package, which
encloses the actual container bearmg the
Uses <3f Radiopharmaceut cal Products 551
Fig 223 Monitoring of commercial radiopharmaceutical package with ionization chamber
survey meter (National Institutes of Health U S P H S )
liquid must be sealed m such a manner as
to prevent leakage of the liquid should break
age of the container occur Those uiteicsted
in the specific regulations applying to ship-
ment of radioactive matenals should consult
the Handbook of Federal Regulations Apply
mg to Transportation of Radioactive Mate
rials published by the United States Atomic
Ener^ Commission There are, m addition
certam regulations imposed by the several
States uhich must be considered m this
regard
Commercial radiopharmaceutical supplieis
h.a.vc condjictad a d^ ot ccsearctl uito
improved packaging methods In general
these research efforts have been directed
toward limiting or reducmg the radiation
hazard to personnel who handle and use
these products and toward reducing the costs
of shipping these materials, along with the
attendant shielding sometimes requited, by
common earners One supplier has put into
use a glass container with a tough coating of
plastic on the outside of the container to pre
vent shatter and minimize, if not elunmate,
the leakage of the liquid contents should the
container be subjected to severe shock or
stress sufficient to break it Another supplier
has developed a shielded outer container
composed oi lead and polyethylene into whidi
the vial containing the radioactive liquid is
placed The glass vial is held securely in the
outer shielded container and is of unique con
structioD to allow the complete removal of
all of the radioactive liquid without even with
drawing the vial from the shielded contamer
In general all radiopharmaceutical suppliers
package sufficient excess matenal m the case
of short half life isotopes so that the amount
ordered is actually available for use on the
day the shipment is received by the user
A variety of commonly used radiopharma
ceutical products is available from commer
cta.1 sources, and the seudet is directed to the.
catalogues and the technical buUetms of these
suppliers for specific details
USES OF RADIOPHARMA-
CEUTICAL PRODUCTS
Medical and pharmaceutical literature con
tarns many reports concerned with specific
purposes and indications for radiopharma
ceutical products In fact there are far too
many such reports m the literature for even
a bnef survey to be made of such uses m
this chapter Mention has already been made
of the official monographs m the Pharma-
copeia of the Umted States These mclude
pr^ucts contammg H’*, Co*®, Au^**, Cr®S
552 Radiopharmacetrticali
and P” in a vancty of forms indicated for
diverse routes of administration, and the
reader is directed to that compendium for
detailed infonnauon concerning these several
products
However, there are many nonofficia! radio-
pharmaccuticals which are commercially
available and arc widely used today At the
present time, the diagnostic uses of radio
active agents far outnumber the well-defined
therapeutic indications It is reasonable to
suppose that the ratio m favor of diagnostic
over therapeutic application of these com-
pounds will contmuci for most authorities
agree that the true potential for diagnostic
and tracer uses of radionuclides m medicine
has not jet been explored Current literature,
in which new uses of radioisotopes m medical
research arc cited indicates the validity of
this belief
A number of the most frequently used non
official radiopharmaceutical products will be
discussed as well as several other tagged
compounds which arc, at present, restricted
to a clinical investigational status
Radionuclidcs Used ts Diagnosis
F c®* Preparations
Radiation Characteristics
Decay Scheme— Oeta particles of 0462
Mev (54*^) and 0 271 Mev (46%)
Gamma rays of 0 191 Mev , I 098 Mev
and 1 289 Mev
Half Life— 45 3 days
This radionuclide is available as Ferrous
entrate Injection Ferrous Sulfate Injection,
Feme Chlondc Injection and Iron Globulin
Ccinp}cx Jn/cct^on Jt js used for a vartety of
ferrokinctic studies, such as plasma clear
ance rate, plasma iron transport rate, appear
ance rate in crytlirocjics and m the deter
mmation of the metabolic state of certain
‘ iron pools’ within the body
Chlormcrodon-llp"''® Injection
Radiaiton Chonctcnstics
Decay Scheme — Beta particle of 0 21 Mev
Gamma ray of 0 28 Mev
Half Life— ts 8 days
Considerable interest in this compound
was generated from the favorable results in
bram tumor localization reported by Blau
and Bender** m 1960 Subsequent studies*®
** ** have also indicated its value in kidney
scamimg as well On theoretical grounds, its
advantages over the more familiar Radio-
lodinatcd Human Serum Albumin USJ*
when used for brain scans include more
efficient counting of the less energetic gamma
tay of Hg"®* (0 28 Mev , as opposed to the
major gamma component of I*®*, which is
0 364 Mev ) , a more rapid blood disappear-
ance rate, with a resultant lower background
in counting procedures, and a lesser incidence
of allergic manifestations, which are some-
times observed in repent studies utilizing the
protein matena! radioiodmated albumm (It
IS interesting to note that the total dose of
chlormcrodrm used m brain scans is seldom
more than and — indeed — is frequently less
than the amount used for sensitivity studies
prior to the initiation of diuretic therapy
using nonradioaciivc chlormcrodrin )
Ca*^ Injection
Radiation Characteristics
Decay Scheme — Beta particles of 0 66
Mev (83%) 194 Mev (17%), 044
Mev (40% Sc«»), and 0 28 Mev
(60% Sc«0
Gamma rays of 1 31 Mev (77%), 083
Mev (6%) and 016 Mev (60%
Sc*')
Half Life— 4 7 days
This radionuclide has recently become
quite popular in the detection of bone me-
tastases Through the use of heavily shielded
scanning equipment equipped with suitable
collimators capable of extremely fine focus-
ing It IS possible to delect even small bone
lesions'® not previously demonstrable with
ordinary X ray studies
1151 Preparations Gljccrjl Tnolcale-I'®'
and Oleic Acid-I*®'
I'®* Radiation Characteristics
Decay Scheme — Beta particles of 0608
Mev (87%) 0335 Mev (9%), and
0 250 Mev (3%)
Gamma rays of 0 722 Mev (3%),
0637 Mev (9%), 0 3 64 Mev
(81%), 0284 Mev (6%),and0080
Mev (2%)
Half Life— ^ 07 days
These two radioiodmated compounds are
widely used m the study of gastromtestmal
Uses of Radiopharmaceutical Products 553
fat absorption m man Tnglycendes mast
undergo hydrolysis before absorption from
the GI tract is possible, while fatty acids can
be absorbed intact The hydrolysis of the
neutral fat, or tnglyceride, is accomplished
m a normal subject by the action of pan-
creatic lipase If, after the oral ingestion of
tnolem-I*®^, senal blood samples taken from
the subject show high radioactivity, good pan-
creatic function and unimpaired mtestinal ab-
sorption IS mdicated On the other hand, if
blood radioactivity is low, either of the fol-
lowmg conditions may exist (1) there is a
deficiency of pancreatic lipase due to abnor-
mal pancreatic function, or (2) pancreatic
function is normal, but there is impaired in-
testinal absorption of the hydrolyzed mate-
nal To differentiate between the two possi-
bilities, an oral dose of oleic acid I*^‘ is
admimstcred If blood radioactivity, as de-
termined by senal blood radioactivity counts,
IS low, absorptive defects m the small intes-
tine are suggested, since the fat was not ab-
sorbed even m the hydrolyzed form
Rndioioduiated Rose Bengal Injection,
When tagged with I‘*‘, this fluorescent red
dye IS a sensitive diagnostic agent for the
diffeiential diagnosis of hepatobihary pathol-
ogies In a normal individual, rose beogal
rapidly disappears from the blood following
mtravenous administration However, m the
presence of liver pathology, its prolonged re-
tention and clearance from the blood follow
characteristic patterns Since it is known that
the uptake and the excretion of this dye are
functions of the polygonal cells in a normal
hver, the rate of blood clearance is a direct
index of hepatic cell dysfunction A major
advantage of diagnostic studies utilizing the
radioiodioated dye is that, through the use of
external gamma ray counting procedures,
blood clearance, liver uptake and excretion
of the labeled dye, as well as its intestinal
accumulation, may be studied simultaneously,
primary hepatic cell injury and extrahepalic
biliary obstruction may also be differentiated
L-TruodofhjTonine-P^*. This radioiodi-
nated thyroid hormone is widely used as a
diagnostic agent for thyroid disease While it
IS not intended as a substitute for other stand-
ard laboratory diagnostic tests, its use makes
possible an additional thyroid function test
which is extremely simple and rapid. It is
well known that thyroid hormonal substances
are bound by plasma proteins and erythro-
cytes This bmding process occurs preferen-
tially, m that thyroxme is more firmly bound
by either the plasma proteins or erythrocytes
than is tniodothyronme It is also Imown that
plasma proteins bind thyroid hormonal sub-
stances more preferentially than do red blood
cells If labeled truodothyronine is added to
the blood of a hypothyroid individual, when
the cells are separated from the plasma after
suitable incubation, it is found that most of
the added radioactive agent is bound to the
plasma proteins and relatively little to the
erythrocytes The obvious explanauon is that,
m hypothyroidism, the secretion of thyroid
honnone is low, leaving the plasma proteins
m a relatively unsaturated state Since the
plasma proteins tend to bmd thyroid hor-
monal substances better than do the erythro-
cytes, most of the radioactivity is found m
the plasma Conversely, m a hyperthyroid
subject, plasma proteins axe nearly saturated
with the hormone, and, hence, most of the
activity introduced with the truodothyromoe
is found m the cell fraction of the blood after
centrifugation Perhaps the greatest single
advantage of the T-3 uptake test, as this de-
termination IS often called, lies m the fact
that It IS performed m vitro, no radioactive
material is actually administered to the pa-
tient Therefore, it can be employed advan-
tageously m studies mvolvmg pregnant
women and children, without regard to any
radiation dose considerations
Sodium lodofaippurate (1*^0 Injection.
This compound is now widely used in kidney
function determmations, often called radio-
isotope renograms It is a simple, rapid and
accurate method of determining renal clear-
ance In addition, this particular chemical
compound is excreted exclusively through
the tadneys, whereas certam other indicators
used in previous attempts to evaluate kidney
function were also excreted partially through
the hver After the dose of labeled compound
has been admmistered intravenously, two
scmtniation detectors are positioned, one over
each kidney The detectors are connected to
a rectilmear recorder and to two count rate
meters The traemgs on the recorder show the
uptake of the compound by the kidneys, and
the recording is continued until the down-
554
Radiopharmaceuticals
ward slope of the curves has been established,
indicaung clearance from the kidne)s The
total tune required for the test is only 10 to
20 minutes One of the most important uses
for this lest procedure is as a screening de-
vice to delect hypertension which may be
due to unilateral renal disease amenable to
surgery
^dioiodinated p-ToIuldme rolyTiii}l-
pjTTolidone (!**') Injection. In certain dis-
ease states, a protein losing gastrocntcropathy
occurs Before the synthesis of a labeled
macromolecule, this condition was extremely
dilEcult if not, indeed, impossible to evaluate
A method for the preparation of such a com-
pound for clinical use in the diagnosis of
this defect has been described' An intra
venous dose of PVP is administered, fol
lowing which the stools of the subject are
collected for a given period of time The de-
tection of radioactive todme in the stools
above a predetermined control level is highly
suggestive of a defect involving protein leak-
ing. smee, normally, the roacromolecule is
not excreted by this route
Tntialcd Vi atcr Injection (II’O)
Radiation Charactenitics
Decay Scheme— Beta particle of 00181
hfev
No gamma component
Half Life— 12 26 years
This product has been widely advocated
as a dia^ostic agent to determine total body
water (TBW) Tritium, or H’, is not me-
tabolized and reaches equilibrium m the
body very rapidly, even in edematous stales
Normal values for TBW vai^ quite widelv,
so that any single delcrmmaiioii may be of
very little value However, changes in the
totm body water of a given subject, clua
dated through senal determinations, repre-
sent rather saluabtc diagnostic mformatmn
It should be mentioned that many of the
commercially available radiopharmaceutical
J iroducts containing P*’ arc also available
abeled with P"-* instead of the heavier iso-
tope The radiation charactcnsiics of P” arc
as follows
Decay Scheme — Beta particle none emitted
Gamma ray of 0 0354 Mev (7*o) and
xray ol 0 0274 Mev (80*^) arc
emitted
Half Life— 57 4 days
It IS mteresting to note that, even thou^
the physical half-life of P** is much longer
than the 8 07-day half life of P**, the radia-
twn dose that is administered to a patient
who receives the compound (or, for that
matter, to the chemical compound to which
the P“ is bound) is much less than that
which evolves from an equivalent amount of
ps* This is due to the absence of a beta
emission in the decay scheme of P'® and, to
a lesser extent, the less energetic electromag-
netic radiation emitted by P'®
Radiowclides Used in Research
Four examples of radiopharmaceutical
products which ate not commercially avail-
able will be discussed, in order to provide
some indication of the research studies which
arc made possible through the use of radio-
active compounds
Kr*® Injection The detection and the
characfcnzaiion of circulatory shunts is an
aspect of cardiovascular medicine that is of
more than passing interest Until quite re-
cently, a clinical diagnosis of anomalies such
as these w'os at best problematical A method
was developed for the formulation of the
radioactive foreign gas, krypton**, into a dos
age form suitable for intravenous adminis-
tration, as a solution of a gas in a liquid *
When injected into the chambers of the heart,
abnormally high levels of activity may be
detected m arterial blood or m expired air
in patients wiih shunts At least one mjec
tion into each chamber of the heart is neces-
sary to detect the site of the shunt The radia-
tion charactcnsiics of Kr“ arc
Decay itAcioe — ffwa parfieiVs of i? f/ itfcv
(O65^o) and 0695 Mev (99+''o)
Gammaray of 0 517 Mev (046*^)
Half Life — 10 27 yean
One of the chief advantages of this test,
besides its sensitivity, lies m the fact that—
although the physical half life of the radio-
nuclide IS quite long — ^when injected in solu-
tion, the biological half-lifc is at most a
minute or two Ihus, relatively large amounts
of the material may be administered without
resulting m a large radiation dose to the
patient
r** Injection
Radiation Charactenstics
Decay Scheme — a positron of 0 65 Mev
energy, which gives rise to two gamma
Other Research Applications 555
photons (annihilation gammas) of 0 51
Mev
Half Life— 1 87 houn
It has long been known that fluonde ion
IS a bone seeker ” In tracer amounts, it has
been shown® that about 50 per cent of the
dose is fixed m bone and the remainder is
rapidly excreted Utilizing this information,
Blau, Nagler and Bender* proved that fluo-
rine** accumulates m bone with a greater
selectivity and at a greater rate than (^cium
and, furAer, that F‘® fluonde concentration
m areas of regenerating bone was at least
ten times that observed m normal bone It
was therefore employed m scanning proce-
dures designed to detect malignant bone
lesions and metastatic bone ^sease and
has produced almost uniformly good results
Because of the extremely short physical half-
life, relatively large amounts (for a bone
seeker) of 0 5 to 1 millicune are adrmnistered
from 1 to 3 hours prior to the scanning
S” Injection
Radiation Characteristics
Decay Scheme — Beta particle of 0 167
Mev
Gamma rays none
Half Life— 87 1 days
A number of investigators have described
a selective retention or slower exchange
(turnover) of sulfate ion in cartilaginous tis-
sue After extensive animal work, it was de-
cided to use radioactive sulfate ion m an
attempt to inhibit the growth of a neoplasm
of cartilaginous tissue, known as a chondro-
sarcoma, in a human subject ^ A dose of one
Cune of S** was admmistered as m
a earner free state and at a pH of 5 0 to a
male Caucasian, 42 years old, with a recur-
ring chondrosarcoma of the nght lumbo-
sacral region The injection was made by the
intravenous route The results of this case,
while not satisfactory m every respect, were
sufficiently mteresting to warrant further
study on other patients In a more recent
case, it was found’® that a more beneficial
effect prevailed — at least from the stand-
point of concentration of the radionuclide in
the tumor at given mtervals post mjcction —
when the dose of S*® was reduced to 500
millicunes, foUovsed by a dose of 2,000 rad
external radiation to the tumor site approxi
mately 2 day s after the mjeaion of radioactive
sulflir had been made In explanatioa of this
phenomenon, it has been suggested that the
more acute effects of the external x-irradia-
tion killed or otherwise disrupted the me-
tabolism of a large number of actively grow-
mg tumor cells, thus further reducing the
exchange or turnover of radioactive sulfur
deposited m the tumor mass Needless to say,
the bone marrow of this subject had been
aspirated pnor to the initiation of therapy to
avoid unnecessary insult to the blood forming
tissue
Cr**-Normal Hnman Serum Albumin In-
jection
Radiation Cbaractenstics
Decay Scheme — Beta particles, none
Gamma ray of 0 32 Mev (8%)
Electron capture
Half Life— 27 8 days
Mention is made o! this compound only
to illustrate the manner m which an attempt
IS made to improve existing products or — as
m this case — to develop a supenor product
for a given mdication This product is used
m a similar manner and for the same purpose
as PVP-I’** Advantages over the earher
compound have been cued,** mcluding a
much simpler synthesis a greater sensitivity
and the fact that a protein (albumin) is bemg
used as an mdicator of a protem leakmg
defect
OTHER RESEARCH APPLICATIONS
There are currently many other uses, both
biologic and chemical, to which radioisotopes
are being put For example, many isotope
dilution studies have been performed m which
the compound of mterest is present in so low
a concentration as to make quantitative esti
mates of concentration impractical or impos-
sible If one adds to this unknown mixture a
knouTi weight of the compound to be mves-
tigated, and this known weight contams an
established amount of labeled, or ‘ tagged,”
molecules of the compound, dilution of the
unknown occurs Then the specific activity
of the dilution is determined by standard
methods, and, when compared with the ac-
tivity added to the mixture, the origmal con-
centration of the unlcnown can be calculated
Radiometric analysis has also frequently
been employed This mvolvcs an analytic
SS6 Radiepharmaceuticals
procedure for a nonradioactivc ion For ex-
ample, nonndioactivc SlI^c^ ion, when pre-
cipiiatcd with iodide, may be detected
with a sensitivit) of 10 ppm of sihcr by ad-
sorption of the precipitate on Fe(OH)s *•
Research methods, m which the technic
of autoradiography is used, are rapidly be-
coming routine in certam laboratones When
these procedures are utilized m radiobiologtc
studies, the localization of radiochemical
compounds in certain tissues can be deter-
mmed by plaang a section of the tissue of
interest in contact with a photographic emul-
sion of suitable type This technic (also
known as radioautography) is widely used
to show the localization of alpha-emitting or
weak bcta-cmitting compounds m biologic
tissues (Fig 224)
Other technics arc used to study diffusion,
reaction kinetics, oxidation reduction reac-
tions, chemical separations and a veritable
host of chemical and biologic phenomena of
mlerest to specialized research groups
LAWS AND REGULATIONS
REGARDING PROCUREMENT
AND USE OF RADIONUCLIDES
The Atomic Energy Act of 1954 assigns
the responsibility for regulating the possession
and the use of source, by-product and special
nuclear materials to the United States Atomic
Energy Commission Regulations issued by
the Commission in these areas arc set forth
m the Code of Federal Regulations (CFR),
Title 10, as follows By-Product hlaterial.
Part 30, Source Material, Part 40, Produc-
tion and Utilization Facilities Part 50, Oper-
ators of Nuclear Facilities, Part 55, Spcaal
Nuclear Material, Part 70, and Standards for
Protection Against Radiation, Part 20 Ex-
cept for By-Product Material, Part 30, which
Will be discussed in some detail, the reader
IS directed to the appropriate parts of CFR
for an explanation of these regulations
By-Product Material is defined by the
Commission as any radioactive matcnal (ex-
cept Special Nuclear Matcnal) produced m
a nuclear reactor or otherwise yielded m or
made radioactive by exposure to radiation
incident to the process of producing or uU-
lizmg Special Nuclear Material These regu-
lations are administered by the Division of
Licensing and Regulation of the USAEC and,
at present, include more than 900 radioiso-
topes of 1 00 elements
No person in the United Slates may manu-
facture, produce, transfer, receive, acquire,
own, possess, use, import or export by prod-
uct matcnal except as authorized m a gen-
era! or a specific license issued by the Com-
mission
A general license concerns possession and
use of small quantities of radioisotopes not
subject to individual licensing There arc a
number of rcstnctions that apply to radio-
isotopes subject to general licensing ( 1 ) No
one may possess at one time more than 10
of the quantities specified in Part 30, (2)
there must be no increase in the associated
rate of radiation effected, (3) the isotopes
must not be used m human beings, (4) they
must not be added to human mgesta or cos-
metics, and (S) they must not be used in any
device for the treatment of human beings or
animals Many educational mstvlutions cur-
rently use isotopes subject to general licensure
m teaching programs
Specific licenses arc issued only on appli-
cation (0 the Atomic Energy Commission A
specific license is reauired for procurement,
possession and use of radioisotopes m quan-
tities exceeding the amounts specified for
general licensure In addition, a specific
license is required for the export of isotopes
of atomic numbers 3 through 83 to coun-
tries or areas wiihm the Soviet Bloc and for
the export of isotopes of atomic numbers
less than 3 or greater than 83, regardless of
their destination Specific licenses may be
narrow or broad m scope That is, they may
cover the use of few or many dilTcrent iso-
topes Like general licenses licenses of this
type also specify a possession limit in each
case
In order to obtain a specific license, the
applicant must complete Form AEC-3 1 3 m
detail This form requires the listing of such
information as ( 1 ) Name and street address
of applicant, (2) department to use by prod
uct material, (3) previous license numbers,
(4) individual uscr(s), (5) name of the
I^diation Protection Officer, (6) by-product
material requested (elements and mass num-
ber of each, chemical and/or physical form
and possession limit requested for each),
Summary 557
Fia. 224. Autoradiograph of thyroid carcinoma (From R. L. Swarm and the National
Cancer Institute)
(7) purpose for which by-product material
will be used; (8) experieoce and training of
individual users; and (9) other information
concerning instrumentation avadable, fadli-
ties and equipment, waste disposal, radiation
protection program; and other data.
If the by-product material is to be used in
human subjects, a Form AEC-313a must
also be completed. The information required
on this form includes: (1) the using phy-
sician’s name; (2) an in(^cation of where
the using physician is licensed to dispense
drugs in the practice of medicine; (3) a de-
tailed statement of the using physidan’s
clinical radioisotope experience; (4) pro-
posed uses, both diagnostic and therapeutic,
including dosages to be employed; (5) the
hospital facilities available for admitting pa-
tients to whom radioactive materials have
been administered; and (6) a description of
identification, processing and standardization
procedures to be employed by the user in the
event the by-product material is not to be
obtained in precalibrated form for oral ad-
ministration or in precalibrated and sterilized
form for parenteral administration.
All licensees are subject to inspection by
personnel of the Commission to insure com-
pliance with the conditions set forth in the
license. If serious violations are found to
exist, the license may be suspended or re-
voked by the Commission.
A number of individual states have also
promulgated Radiation Safety Codes, the
regulations of which must also be obeyed by
licensees.
While this degree of control may seem to
be excessive, the enviable safety record ac-
cumulated by radiation workers and the nu-
clear energy establishment in general indi-
cates the wisdom of such control measures,
for few industries can compare favorably in
this regard with the nuclear energy industry.
SUMMARY
Information has been presented to give the
reader a better understanding of the practice
of radiophannacy. The text is not intended
to be comprehensive in scope, and detailed
explanations of the medical uses of radio-
pharmaceutical dosage forms have been pur-
posely avoided. The reader is directed to the
references cited and to the general bibliog-
raphy listed at the end of the chapter for
more detmled information on these matters.
558 Radiophormaceufieolt
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2 Andrews, J R., Swarm, R Schlachter,
U, Brace, K. C. Rubm, P, Bergenslal,
D M , Gump, H , Siegel, S , and Swain,
R \V The effects of one Cune of Sulfur
35 administered intrasenously as sulfate to
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3 Bell, C G , Jr , and Hayes, F H Liquid
Scintillation Counting — Proceedings of a
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5 Blau, M , Nagler, W , and Bender. M A.
Fluonne-18 A new isotope for bone scan-
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Waldmann T Fnnciples in the Produc-
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Institutes of Health Radiation Safety
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33 9, 1961
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Radioisotopes and Nuclear Techniques in
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USAEC Contract No AT(11-I).737,
Lafayette. 1960
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and fiaughlin, J S Detection of bone
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454, 1962
16 Fields, T, and Seed, L. Qinical Use of
Radioisotopes, Chicago, Year Book Pub ,
1961
17 Fowler, J M , et a! Fallout — ^A Study of
Superbombs, Strontium 90, and Survival,
New York, Basic Books, 1960
18 Fnedlander, G, and Kennedy, J W
Nuclear and Radiochemistry, New York,
Wney, 1955
19 Hayes, F N Solutes and Solvents for
Liquid Scintillation Counting, Packard
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iMDt Co , Inc , La Grange, Illinois, rev
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20 Haynie, T P , Stewart B H , Nofal,
M M , Carr, E A , Jr , and Beierwaltes,
W H Renal scintiscans in the diagnosis
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21 Hine G J , and Brownell, G L Radia-
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22 International Commission on Radiological
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6, 1955
23 McAfee, J G , and Wagner, H N , Jr
Visualization of renal parenchyma by
scintiscanning with Hg 203 Neohydnn,
Radiology/^ 820, 1960
24 Maximum Permissible Body Burdens and
Maximum Permissible Concentrations of
Radionuclides in Air and in Water for
Occupational Exposure Handbook 69,
National Bureau of Standards, U S De-
partment of Commerce Washington, 1959
25 New atul NonnfQciai Drugs, Ptwladelphii,
lappmcott, 1963
26 Pharmacopeia of the United States, 16th
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27 Radioisotopes — Special Materials and Serv-
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Revision, 1960
28 Radiological Health Handbook, FB
I21784R, U S Department of Health,
Education and Welfare, U S P H S ,
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29 Recommendations of the ICRP. Report of
the Committee on Permissible Dose for
Internal Radiation, London, Pergamon,
1958
30 Report of the International Commission on
Radiological Units and Measurements
(ICRU), Handbook 62, National Bureau
Bibliography 559
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32 Seaborg G T Third Annual Nuclear
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33 Shapiro, B USAF School of Aviation
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34 Sklaroff, D M , Berk, N . and Kravitz, C
The renal scintigram in urologtc work up,
JAM_A 178 418,1961
35 Strominger, J M, Hollander, J M, and
Seaborg, G T Table of isotopes. Re-
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Behrens, C F Atomic Medicine, Baltimore,
Williams &Wakms. 1959
Beierwaltes, W H , Johnson, P C , and Solan,
A J Clinical Use of Radioisotopes, Phila
delphia, Saunders, 1957
Blatz, H Radiation Hygiene Handbook, New
York, McGraw Hdl, 1959
Chase, G D , and Rabmowitz, J L Principles
of Radioisotope Methodology, 2ad ed , Mtn
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Harvard Umv Press, 1957
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Lapp, R E , and Andrews, H L. Nuclear
Radiation Physics, Englewood Cliffs, Pren
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1960
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Quimby, E H , Feitelberg S , and Silver, S
Radioactive Isotopes in Medicine and Biol
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Quimby, E H Safe Handlmg of Radioactive
Isotopes m Medical Practice New York,
MacnuUan 1960
Shy, G M , Bradley, R B , and Matthews
W B , Jr External Collimation Detection of
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Index
Absorption of drug, evaluation,
by unnary excretion method,
149
gastrointestinal, effect of Dpid
solubility, 55
emptying rate, 42-43
in evaluation of dosage forms,
80-81
influence of dietary factors,
79 80
role of regions, 40-42
kinetics, 32 36
liquids, from gastrointestinal
tract, 69 71
ointments, by skin See Oiot
rnents, effect on skin, general
factors affecting absorpuon
processes, 38-40
diffusion passive, 38 39
pinocytosis, 40
transport. acUvc, 38, 39
facilitated, 40
rate, 34
eflect on drug action, 36 38
evaluation from drug level
data, 51
total amount, calculation, 37
Acacia 184 190. 308
Accreditation Standards for Rest
dency m Hospital Pharmacy,
523
Acetaldehyde, structure, 314
Acetamide, dissociation constant,
330
Acetaiulid. dissociation constant,
330
Acetest reagent tablets, 450
Acetic acid, dissociation constant,
318
incompatibility, 318
solubility, 317
stmclure, 323
Acetone, solubility, 316
N Acetyl p aminophenol, 47
Acetylcholine, 146 147
chloride, solubility, 340
structure, 343
Acetylsalicylic acid, and aluini
num aspir. dissolution, 60
incompatibility, 323
solubility, 321 323
(ablet form, gastrointestinal ab-
sorption disintegration and
dissolution values, 74, 75
Aads, weak, absorption in gastro-
intestmal tract, 40
See abo individual names
Acridine dyes, 353
locompatibili^, 359 360
Acnflavine, hydr^hlonde, struc
ture,3S3
solnbiliiy. 358
structure, 353
Acromycio. See Tetra^line
Adeps Sobdus, 232
Adhesive tape removers m aero-
sols, 281
Administration of drugs, fre-
quency. IS
route, 17 18
sequence accordutg to Latin
square design. 79
Adrenalin See Epuephnne
Adsorption of drugs, on diluents,
Aerohaler (Abbott), 439, 440
Aeroso’s,241 286
containers. 272 275
defloitioos, 242 243
histoncal considerations, 243
245
manufacture procedures, 251
259
laboratory, 251-259
cold process. 251-255
pressure process, 254-257
laipe scale, 255 259
medianal, 243, 283 285
advantages, 245 246
operation mode, 246 253
phannaceulical, 243, 277-263
advantages, 245
cfassificauoQ, 281 283
propellants, classification of
compounds, 272
compressed gas, 270-271
carbon dioxide, 271
rutrogen. 271
nitrous oxide, 271
physical properties, 270
liquefied gas, 258 270
fiuonnated hydrocarbons,
258 270
cbeinscal properties,
268 270
mixed with hydrocar-
bons, 270
nomenclature, 259 260
561
Aerosols, propellants, liquefied
gas, fluorinated hydrocarbons,
nomenclature — (Continued)
numencaldesignation,
260
physical properties, 260-
265
density, 264 266
heat of vaporization,
266. 267
solubility cbaractenstics,
266,268
vapor pressure, 260-
265
range of vapor pressures
obtainable with van
ous nuxtures, 260
with surfactant, 279
without surfactant, 278
pbysieochenucal properties,
256, 258 273
toxicity, 271 273
systems, classification, 246
compressed gas, 248 253
dispensing, by foam, 251
by solid stream, 249 251
by spray, 252 253
liquefied gas, 246 249
three-pbase 247 249
foam, 248 249
two-layer, 247-248
two-phase, 246-247
dispersion or suspen
sion, 247
tests, special 286-287
valves, 273-274, 276 277
foam, 276
metered, 276 277
spray, 264, 276
vetennary, 285 286
Agar, 190. 307-308
Age of patient, effect on elimina
Hon of drags, 46
as factor in calculating dosage,
17
Albamyxin See Novobiocin
Alcohol(s).306 310
boiling point, 328
monohydne, solubility, 307
monohydroxy, 306
polyhydroxyl, 306-310
carbohydrates, 306-310
562 Index
AiedboHt)— (Continued)
tolubilitv, compamon with a1
dehydes, 313
Aldchyde(i), 313 316
chemutiy, 313 314
cyanohydnn. structure, 313
incompatibility, 314>316
solubility, 313
compansoQ with alcohols,
313
Aldehyde-bisulfile compound,
structure 313
Algins. 185, 191
Aliquot method of weighing and
measunng, 20-22
Atkah metals, 293 294
incompatjbiliues, 293 294
Alkaline earth metals, Incompati
bihties, 294-296
Alkaloids, 331 332
and chemically related com
pounds, 331 342
classification, 332 338
croup, alkanolamine, 333
334
alkylamtne, 332
aniLne, 338
djphen^lalkylsmine, 333
piaaidine, 338
imidazole, 337
indole, 336 337
isoquiooline, 33S 336
pheaothiazine, 338
phenylalkylamine, 332 333
piperidine, 337 338
punae, 338
pyrazole, 337
pyndine, 334
]^dine pyrrolidine, 334
condensed (tropme),
334 335
quinoline, 335
incompatlbiliiy, 338 339, 342
solubility, 340-342
Alkanes, boiling point, 328
Alkanolamioes, structures, 333
334
Alkylaminea, siruclures, 331
Aluminum, chloride, 299, 300
compounds, solubilities, 301
hydration energies, 300
hydroxide gel 300
incompatbilities 299 300
ionic i^iiis, 300
phosphate, 299, 300
salts, 300
subacetate, 300
sulfate, 299. 300
Alurate, solubility, 349
structure, 347
Amaranth, resistance to condi
lions influencing color stabil
lty.359
Amaranth— (C<m//nir«f)
solubihQi. 358
structure, 354
American Association of Dental
Examiners, 383
American Assouation of Dental
SchooU, 383
American College of Surgeons,
476, 477
American Dental Association,
Couoat on Dental Education,
383
American Hospital Association,
477, 484, 485
American Journal o/ Hospital
Pharmacy, 477
information on dosage forms,
86
Amencan Medical Assoaaljon,
485
Amencan Pharmaceutical Assoa-
auoQ, 477. 484
Code of Ethics. 381
Amencan Society of Hospital
Pharmacists, 477-478, 484
Amencan Standards Assoaation, 8
Amencan Vetennary Medical
Association, 393, 3M
Attudopynne See Amioopynoe
Armaes. 329 331
solubility, 329 331
p-Asunobeazoic aad (PABA),
47. 374
Aminopyriae. solubility, 340
structure. 337
p Amiflosah^he acid, 50
Ammonium chlonde, 49
Ammonium hydroxide, dusocia
tion constant. 330
Ammonium salts, 293 294
solubility, 293
Amobarbital, solubility, 349
structure. 348
Amphetamine. 71
solubility, 340
structure, 332 333
Amyl alcohol, solubility. 313,
316.324,328
n Am^ alcohol, solubilifr, 330
Amyl Ditnte. incompatibdity, 527
n Amylamine, solubility, 330
Amylcaioe See Amylune bydro-
chlonde
Amylsine hydrochlondc, tolubd
ity, 340
ttructuiT. 334
Amytal 5ee Amobarbital
Analgesics, in dentistry, 385
narcotic, flavonng. 164
non narcotic, flavonng, 164
In podiatry, 392
Androstanolone, 71
Anesthesin See Ethyl aminoben
zoate
Anesthetics, local, in aerosols, 281
Aneuno, 3TJ 378
Amhne, dissociation constant, 330
structure, 330, 338
Anti acrodynia rat factor, 376
Anti arthritic, 397
Anti asthmatic bronchial, 398
Antibenben vitamin, 377 378
Antibiotics, 365 371
bacitracin. 366
chloramphenicol, 366
cydosenne, 366 367
erythiomyan. 367
flavoring, 164
neomycin 367
novobiocin. 367 368
oleandomycin. 368
pemcillio, 368 369
m podiatry, 392 393
polymyxin 369 370
streptomyem, 370
tetracyclines, 370-371
lyrothnciD, 371
Antieczematous agents, 202
Antihemorrhagic vitamin, 373
Antihistamine 395, 396
flavonng. 1 64
use m dentistry, 386
Anlj infectives, 397
m podiatry. 392 393
use in denustjy, 385
Anti inflammatory agents, use m
denustty, 386
Antineuntic vitamin, 377*378
AntjparasiUcs, 202
Antiprunue agents, 202
Aniipyrine, solubility, 340
structure, 327, 337
Antirachitic vitamm, 372 373
Antisebonheics, 202
Anusepucs, 202
m aerosols, 281
Antimony incompatibilities 302
Antuerophthalmta vitamin, 372
Anireny], structure, 343
Apomorphine hydrochloride, tot
ubiliiy, 340
structure, 336
Apolhecanes system, 3 5
calculations w/w in, 7
equivalents, 8
Argyrol, 365
Armstrong Suppository Machine
No 3,237
Aromatic carboxylic acids, them
istry, 321 324
dissociation constants, 322
solubility, 321
Arrfaemus equation, ]62
Arsenic, Incorapatiblhues, 302
Arsenic acid. 302
Arsenous acid, 302
Ascorbic aad 374
Index 563
Aspirator, nasal, for mfant, 411?-
420
Aspinn See Acetylsalicylic acid
Atomic Energy Act of 1954, 55^
Afomizen, 434-437
solutions compatible with me^
als, 436
Atropine, solubility, 340
structure, 334
Aureomyan 5eeChlortetracycliDe
Autoxidation reactions affecting
stability of solutions, 161-162
Availabibty of drugs, biologic, it*
evaluation of dosage forms, 8^
Azo dyes, 353 355
incompatibility, 360
Azobenzene, structure, 360
Bacitracin, 366
Bandage(s), adherents, in aen?
sols, 281
absorbent, adhesive, 453
conforming, 458
elastic, 427
plaster of Pans, 458 460
roller, 457
self adhenng 458
tnangular, 457
tubular, 456-458
Banthine Bromide See Methari
thelme bromide
Barbital, solubility. 349
structure, 348
Barbiturates, 347 350
chloroform water partition co
efficient of uodissociated
drugs, 55
colomc absorption lo rats, 55
effect on biotransformatiou
rates of drugs, 47
ffavonng 164
incompatibility, 349 350
refill regulations, 24 25
solubility, 152, 349
Banum, 294 296
salts, 295, 296
Bases, weak, absorption in gas-
trointestinal tract, 40
Basins for sickroom use, 430
Baumfi, Antoine, 226
Becquerel, Henn 526
Bedpans, 429-430
Benadryl Hydrochlonde. See D»
pheEhydcamine hydrochlonde
Benedict test of unne, 449
Benemid See Probenecid
Bentoiute, 187, 217
Benzalkomum chlonde, solubil
ity, 340
structure, 344
Beozednne See Amphetamine
Benzethomum chlonde, solubil
ity, 341
structure, 344
Benzocaine See Ethyl anuno-
benzoate
Benzoic aad, 41
dissociation constant, 322
incompatibility, 322
solubility, 322
Benzpynniiim bromide, structure,
343
Benzyl benzoate, incompatibility,
325 326
Betanaphthol, incompatibdity,
312
soIubiLty, 312
Bevidox See Vitamin Bjg
Biebnch Scarlet. See Scarlet Red
Sulfonate
Biebnch Scarlet Red See Scarlet
Red
Bilirubin, 53
Binder, addition to tablets. 120
hiologtca} Ahstracts, information
on dosage forms, 87
Biopharmaceutics dcfimtion, 31
Biotm. 374 375
Biotransformatioo, 44-49
classification, 44
effects of factors, age of pa
tient, 46
disease, 47
dosage. 46
drugs. 47-4$
dunog gastroiiilestiRa] absorp
tion, 48-49
rate, effect of preadmuustered
barbiturates on, 47
Biscoumacetate, 47, 50
Bismarck Brown, solubility, 358
Bismuth, incompatibilities, 302-
303
salts, 302 303
Blood, drug concenlratiou,
changes in, 32 36
levels as biologc factor in
dosage form design and
evaluation, SI 54
data, use in evaluation, of
absorption time of
drugs, 51
of antibiotics, 53 54
Body rubs, in aerosols, 281 282
Borax, 111, 299
Bone acid. 299
m ophthalmic solutions, 174
Boron, incompatihiliUes, 299 3Q0
Breast pomps, 418. 420
Bnlliant Bine, resistance to con
ditions influcRcing color sta
bihly, 359
FCF. solubifaty. 358
structure. 357
Bromphenol Blue, solubili^, 358
structure. 356
Bronchodnator. antihistaminic,
396
Bums, remedies, in aerosols, 282
Busher Automatic Injector, 442,
448
Butacame sulfate, solubili^, 340
structure, 333-334
Butane, boiling point, 328
solubili^, 328
Butesin See Butyl ammobenzoate
Butyl alcohol, solubility, 313,
316, 324, 328
n Butyl alcohol, solubility, 330
Butyl ammobenzoate, solubihty,
340
tt Butyl stearate, camauba wax
and steanc acid mixture as
entenc coating for capsules
and tablets, 136 137
R Butylamme, solubih^, 330
Butyn See Butacame sulfate
Butyraldehyde. solubility, 313
Bu^ic acid, solubility, 317
Ca<t injection, 552
Caffeine, solubility, 340
structure 338
Cakjng, m pharmaceutical sus
pensions, 179
Calciferol. 372
Calcium. 294 296
absorption from gastrointestinal
tract in normal and anaod
subjects, 69 70
salt. 295
Camphor, 113 114
incompatibility, 317
solubility, 317
Canes, 464
Capnc acid, solubility, 317
n Caproaldehyde, solubility, 313
Caprokol See Hexylresorcmol
Caproic and solubility, 317
CapryLc acid solubility, 317
Caps, cervical 426
Capsules. 72 73. 103-108
capacities 104
coating See Solids, as dosage
form coating
counting machine, 491
elastic, 107
extemporaneous, 104 107
filling, 105 106
hand-operated machine. 105,
t06
handling, precautions, 105-106
hard gelatin, 104
specialty names, 108
vials, use m dispensing, 106-
107
weight, accurate, U.S P tol
erances, 127-128
Carfaachol, solubility, 340
structure, 343
Carbmol base, structure, 362
564 Index
Carboh)drate», 306-310
IncompatTbltities, 307-310
$u|ari See Sngan
Carmn dioxide as propcllaot m
aerosols, 271
Carbonate esten, solubility. 327-
328
Carbonic actd. dissociation con
slants, 311
ester of ethyl salicylate, solu
bilily, 327 328
Carbopof, 188
Carbowax, 216-217
Carboxylic acids, 317-324
aromatic, 321 324
dicarboxylic. 320
hydroxy polyxarboxyhc, 320-
321
monocarboxylic (fatty acid
series), 317 320
Carboxymelhylcellulose, 186,
309 310
Carotenes, 372
Catalysts in pharmaceutical solu
tions 160-161
Catheter(s). filiform, 421, 422
flexible. 421, 422
Foley. 421, 422
induellinc, 421
Maleeoi lip, 421
mushroom bp 421
sizes, 420, 422
urethral, 421, 422
Catheterization urinary infections
from, 422
Catholic Hospital Association,
477
Cathomycin Sodium Set Novo
biocia j '
Cccon, 175
CcdilamdO, 17S
Ccepryn See Cetylpyndinium
chloride
Cellulose, acetate phthalate as
entcnc coating for capsules
amliaWerx. UH-W
derivatives, 308 309
gum, 309 310
microcrystalline. 186 187
Cerates, 222
Cetylpyndinium chlonde, struc-
ture. 344
Cevitamic acid, dee Ascorbic acid
Charioite ND ! sanitary model
colloid mill, 181, 182
Chemical Abstracts, information
on dosage forms, 87
Chemical Spccialucs Manufat-
turen Association, 258
tests for aerosols, 287
Chilsonator, 124
Chiropodist Adhesive Felt, 434
Chiropody See Podiatry
Chloral, structure, 314, 315
Chloral atcoholate. incompatlbil-
ity,3lS-3l6
structure, 315
Chloral hydrate, incompatibility,
315-316
solubility, 315
Chloramphenicol, 46, 47, 62, 366
esters of. 63
palmitate. 61, 62
ester, 146
Chlormerodnn injection,
552
Chloroacetie acid, dissociation
constant, 318
p-Chtorobenzaldoiime. 63
Chloroform, structure. 316
Chloroguanide hydrochloride, sol-
ubility. 341
structure, 338
Chloromycetin See Chloram-
phenicol
Chlorothiazide, 46
Chlorothymol, 312
Chlorotrianiscne, 146
Chlorpromazine hydrochlonde,
solubility, 340
structure. 338
Chtorpropionie acid, dissociation
constant, 318
Chlortetracycline, 370
Cholesterol. 192
Choline, 375
Cholinesterase. 147
Chondrus. 190
Cinchotudioe, solubiUty. 340
sulfate, structure. 333
Cinchonine, solubility, 340
sulfate, structure. 335
Citnc .icid 320-321
dissociation constant, 319
Incompatibility. 321
solubility, 319 321
structure, 323
Clark's Rule for calculating dos
age, 17
Clays as stabiliuug agents for
suspensions, 187-188
Clinical Pharmaeolo/ty and Ther’
apeutlcT, information on dos
age forms 85
Clinisiix, 450
Gimtnt tablet. 449
CMC. 309 310
Cobtone See Vitamin Bjj
Cocoa butter decTheobroma oil
Cocaine, solubility, 340
structure. 335
Codeine solubility, 340
structure. 335
Colchicine, structure. 336
Colloids, poteclive, 182, 184 188
classification. 184
Color, addiuon to tablets, 120
Coloring, solutions, 163
tablets. 133
Colostomy, apparatus and irriga-
tion set. 417
vs ileostomy, basic dilTerences,
415
Compazine Injection, 175
Compicxstion of drugs, 64 66
interaction with a macromo-
lecular substance, 64 65
solubility changes, 65 66
stability constant for. 64
Compounds, ammonium, quater-
nary, 342 345
incompatibility, 345 346
solubility, 344
hydantoin, 350 351
inorganic, mcompatibililies,
292 304
alkali metals, 293 294
alkaline earth metals. 294
296
hydroxides, comparison
of hydration energy
and solubilities. 294
solubilities of salts 294,
295
sulfates, hydration, sol-
ubility and lonie iize,
295
arsenic, antimony and bis
muih, 302
boron and aluminum, 299
300
general solubility rules,
292 293
Iron nickel and cobalt,
303 304
tin and lead, 300 302
Zinc and memiiy, 296-
298
hydration, 296 298
and salts properties,
299
solubility. 297
'iiltfvppinnniatninti, v.'ibiv,
345-351
barbiturates, 347-350
hydantoin compounds,
350 351
sulfonamides 345-347
basic. 329 345
alkaloids and chemically
related compounds,
331-342
amines, 329 331
quaternary ammonium
compounds. 342-345
organic, incompatibilities, 305-
378
Concentration of drugs, changes
m blood, 32 36
constant, in fluids of distribu
tlon. 45
Index 565
Condoms 424-425
Cones medicated use m home
opathy, 389
Congo Red solubility 358
structure 354
Coniine solubility 340
structure 334
Contraceptive agents 426
Cortisone acetate polymorphic
forms 61
Cots finger 424
Coulombs Law 153 154 157
Council oa Dental Education of
the Amencaa Dental Associa
tion 383
Counting machine tablets and
capsules 491
Cowlings Rule for calculating
dosage 17
Cr®' nomal human serum albu
tmn injection 555
Creams 222
Creosol structure 328
Creosotal 328
Creosote carbonate 328
incompatibibty, 312
Cresol mcompatibilily 311 312
Cnmper hand-operated for alu
mioum seals 490 491
Crutches 461-464
accessories 46M64
handlmg on stain 463
size estimation standard chart
462
Crystal form of drugs 60-62
Crystal violet, structure 356
Current Contents information on
dosage forms 86
Cushions invalid 413-414
Cyanocobalamin See Vitamin
®I2
Cyclomethycame See Surfacame
C^Iosennc 366 367
Deflocculating agents, 179
Degradation of stability of solu
tions hydrolytic 161
micro-organisms growth of
162 163
temperature eSect of 162
Deh^uescence 110 111
Delvinal solubility 349
structure 348
Demerol Hydrochloride See Me
pendine hydrochlonde
Dcmelhylchlortetracyclme 370
371
effect of serum on antibac
lerial activity 53
Dentistry pharmaceutical prepa
rations used m 385 387
practice pharmaceutical serv
ices to 384 385
Dermatologic products in aero
sols 282
Desoxyephednne See Metham
phetamine
Dextro propoxyphene use in
dentistry 385
Dextrotest 449-450
Diabetes mellitas diet factors
449
incidence 448
supplies for management 448
449
unne tests 449-450
Dial solubility 349
structure 348
Dialysis of complexed drags 64
65
Diapers disposable 460
Diaphragms vaginal 425-426
Diathermy short wave 467
Dicarboxylic acids 320
Dichloroacetic acid d ssociation
constant 318
Declomycin See Dcmcthylchlor
tetracycline
Dicodid See Dihydrocodeinone
Dicumarol 37 47-49
Dielectric constant changes of
solvent 155 156
of Iicruid 154 155
Diethoxin See ffifraeaine hydro-
ehlonde
Diethyl ether bo1me point 328
incompatlbilitv 329
solubility 328
D ethylamine dissociation coo
stint, 330
Diffusion of dines across bio
loeic membranes 32 33
concentration gradient 32
equtlibnum 33
passive 39
Dieitallioe Hativelle 175
DTiydrocodemone, structure 336
DTiydromorphinonc hydrochlo-
nd“ solubility 340
structure 336
Dihydroxyethyl peroxide struc
ture 329
D hydroxysDCcinic acid incom
patibihty 320
Dilanlm See Diphenylhydantoin
sodium
Dilaudid See Dihydromorpbi
none fiydrochlonde
Dilutions, use m homeopathy
388 389
Dimethicone as oleaginous base
211
Dimethyl ether boiling point.
328
solubility 318
Dimethyl ketone 316
Dimethylamine, dissociation con
stant 330
Dimelhylcthylamines structures
332
Dioctyl sodium sulfosuccinate 68
Diomn See Ethylmorphine hy
drochlonde
Diothane hydrochloride solubil
ity 340
Diothane structure 337 338
Diphenhydramine hydrochloride
solubility 340
structure 332
Diphenylalkylamines structure
333
Diphenylhydantoin sodium solu
bihty 351
structure 350
Dipole moments 153 154
D scare effect on elimination of
drugs 46
Disinfectants lO aerosols 281
Dismtegrant, addition to com
pressed tablets 120
Disintegration of drug con
trolled, as method of
release 141 143
Medules 143
repeat action tablets 14!
142
Spansules 142 143
in tablets 73
Disks medicated use in home
opathy 389
D s^ium salt structure 361
Dispersion of drugs eutectic mix
lure 72
solid ID liquid See Suspensions
Displacing agents 53
Dissociation constantfs) of
drugs 54 56
aromatic carboxylic acids 322
bases, organic, 330
monocarboxylic aads and
chlonnated denvatives 318
phenols 311
polycaiboxylic acids 319
Dissolution of drugs 150 153
rate 56 60
influences deposition of u-a
ter soluble film on sur
face 59 60
formulation factors 74 75
methods for changing pH
in d fTusion layer 57 58
salts of weak acids S8
solubility m d ffusion
layer 57 58
surface area, 56 59
modificauon 72
Distnbuuon of drugs, apparent
volume 33 34
Dodex See Vitamin B|«
566 Index
Dolinlhifl. Stt Mcperidjne by-
drochlonde
E>oIq)hine See Methadon
Do«aj*, c&lculatiO&s. 7 9
evaluation, factor?, 290
formfs), 18
aerosol? 5er Aerosol?
capsules. See Capsule?
clinical evaluation. 76*8i
expenmenlal. 77 80
conditions, 79 80
controls, 77
data. 83 85
statistical analysis,
83 84
validity of conelu*
sions, 84 85
methods, 80-83
absorption rate, gas-
trointestinal, 80-81
biologic availability,
excretion rate, 80-82
sensitivity, 83
side-elfects, 82 83
stability In gastroln
tesuoal tract, 81
placebos, 77-78
selection of subject?, 77
technics, 78-79
test methods, objective vs.
subjective, 78-77
deflniUoB. 31
design and evaluation, 31-
87
biologic facton, 38 54
physical and chemical fae-
tors, 54-89
elTect(s), on drag conccntra
tion in blood, 38-37
of surface active agents,
88-89
emulsions, factors In avail-
ability of drags, 71
(nformaiion sources, 85-87
liquid See Liquid, as dosage
form
maintenance doses, 44
major classes, 69
pharmacologic effect, influ-
ences on, 31. 32. 36
repeat action, vs sustained-
release. 139
technics of obtaining, con-
trolled disintegration,
14M43
semlsohd See Semisotids, as
dosage form
solids. See Solids, as dosage
form
solution See Solutjon(s)
suspensions, 70-71
sustained release. See Sus-
tained release pharmaceu-
ticals
Dosage, forni(s) — {Continued)
tablets, compressed, 73-76
overdosage as therapeutic in-
compaubsltiy, 290
Oouche(s). powtera, 100
vaginal, pans, 430
sjTinge, fountain, 409-412
rubbtf bulb. 418. 419
Dramamine Injection, 175
Dressings, surpcaL bandagefs),
adhesive absorbent, 453
confonning. 457, 458
plaster of Pans, 458-460
roller. 457
Mif adhenng. 458
triangular, 457
tubular. 456-458
cellulose. 452
Chiropodist Adhesive Felt.
454
cotton. 451-452
gauze, absorbent (cotton),
451. 452
pads, 451-453
spcctsl. 453
liquid adhesive. 456-457
moleskin, 454
packaging and storage, 460
pad?, eye. 4S3-454
gauze. 451-453
plasters, adhesive, 454-455
reactivity to, 455
primary, 452^54
ravott, 452
related supplies, 480-461
diapers, disposable, 460
masks, surgical, 460-461
underpads, disposable.
460
secondary, 454-460
tapes, hyporeactive. 456
Drop as unit of volumetnc meas-
ure, 8
Droppers, medicine, official and
standard, 8 9
Drugs, absorption See Absorp
lion of drags
activity, pharmacologic, influ
ence of route of ad
miiuslration. 50-51
rate of decline, 49
biologic availabiliQr, 37-38
local side-effects. 38
biologic half life. 35, 44-45, 48
concentration, effect on means
of absorption. 40
content, changes in. 34-35
total, calculatKm, 33
diffusion See Diffusion of
drags
elimination See Etunuution of
drugs
"therepexrtic blood level,*' 36
transfer processes across bio-
logic membranes, 32-36
Drugs of Choice, information on
dosage forms, 86
Durabond products. 145-146
Durham Humphrey Act, 24, 500
Dyes, 351-363
acndine, 353
incompatibility, 359-360
atixochrome, 352
azo. 353-355
incompatibility, 360
classiflcaiion, 353-357
“coal tar," 351
fluorescein, 355
incompatibility, 357-363
tndigoid, 357
incompatibility, 363
mtro, 357
incompatibility, 363
phthalem, 355 356
incompatibility, 380-361
rosanlline, 356-357
solubility, 358
theoiy of color, 351-353
thlazine, 356
incompatibility, 362-363
trphenylmcthsne, 356-357
locompaubility, 361-362
Ebers Papyrus, J
EDTA, effect on drag absorption
in gastrointestinal tract, 66
Education, dental, pharmaceuti-
cal services to, 383-384
medical, pharmaceutical serv-
lees to, 382
Efflorescence, 111
Elastic supports, 426-430
athletic, 429
bandages, 427
for extremities, 428
hose, 427-428
suspensories, 428-429
Elavil Injection, 175
Elimination of drags, effect of
factors, age of patient, 46
disease, 47
dosage, 46
in evaluation of dosage forms,
81-82
kinetics, 32 36
rate, 34 35
unnary excretion, rate, 35
Elonne Sulfate See Tricyclamo!
sulfate
Emollients, 202 203
Emulsions, 178, 188-198
agents, from animal sources,
191-192
classiflcation. 189
natural, from cellulose, 191
from vegetable sources,
189-191
^(hetic, 193-198
Index 567
Emukiom, agents,
qmthetic — {Continued)
amonic, 193*195
compounds, sulfated,
194*195
sulfonated, 195
soaps See Soaps
cationic, 195
nomonic, 195
esters, glycol, 197
sorbitan, 197*198
HLB (bydrophile-
lipophile balance)
^tem, 195-197
availabOity of drugs contained
in, 71
bases, 214*216
specialty, 216
dispensing, 199
globule size, 189
packaging, 199
phase volume ratio. 189
preparation, general, 198
preservation, 198 199
solids, finely divided, 192*193
stability factors, 189
storage, 199
vucosity, 189
Enema, disposable units, 41M12
synoge, fountain, 410*411
Energy of hydration, definiuon.
293
Enterostomy outfits, 414*418
colostomy apparatus and ir
ngation set, 417
diagrams of typical enterosto-
mies, 416
Eosin, soluble, solubility, 358
structure, 355
Epfiednne, solubility. 340
structure. 333, 346
Epmephnne, solubibly, 340
structure, 333
Epimne, sofubifity, 340
structure, 333
Epitrate "Ophthalnuc," 175
Ergometnne See Ergonovine
Ergonovine, maleate, 336
solubility, 340
Ergotamine, solubility, 340
Ergotamine tartrate, 336
Ergotoxine, solubiLty, 340
structure, 336
Ergotrate See Ergonovine male-
ate
Erosion of drug as technic of re-
lease. 143 144
Erveka equipment for omtment
preparation, 2l9
Erythroan See Erythromycin
Erythrol tetranitrate, 63
structure, 327
Erythntyl tetranitrate. structure,
327
Eiythromycm, 56, 367
esters of, 63
Eiytbrosin, resistance to condi
tions mfluencing color sta*
bihty, 359
solubility, 358
structure, 355
Esenne See Pbysostigmme
Esenne saliqrlate, structure, 336
Esmarch tnaoguiar bandage, 457
Esomid Chloride See Hexa-
methomum cUonde
Esters, 324 328
denvation, inorganic acids,
326 328
incompatibibty, 324 328
solubili^, 324. 326
organic a^s, 324*326
glycol, 197
sorbitan, J97 198
Etamoo. See Tetraethylammon*
lum chloride
Eiamon Chlonde See Tetraethyl
ammomum chlonde
Ethers. 328 329
boding point. 328
incompatibiLcy, 328 329
solubility, 328, 329
Ethocel, 309
Ethyl acetate, solubility, 324
Ethyl alcohol, dissooation cos
stants, 311
in hospitals. Federal code and
regulations. 500
soIubihty,313,316, 330
stilly Federal code and regu
lations, 500
Ethyl aminobcDzoate, solubility,
340
Ethyl biscoumacetate, 53
Ethyl methyl ether, boiling point,
328
solubili^, 328
E4b}'} Bioifbiae bj'dnxblonde,
solubiLty, 340
Ethyl mtnte, mcompatibiLty,
326*327
Ethyl nitrite spirit, mcoropalibil*
ity, 326-327
Ethyl saLcylate, mSueoce of
moisture on pemitaneoos
absorption rate, urinary se-
cretion data. 206, 207
structure, 328
Etbylamine, dissociation con-
stant. 330
solubility, 330
Ethyl n butyl etber, boiling point,
328
solubility, 328
Ethylcellulose, 309
Ell^lidene peroxide polymer,
structure, 329
Ethylmorphine hydrochloride,
structure, 335
Eucupm, solubiLty, 340
structure, 335
Euresol. See Resorcmol mono-
acetate
Excretion of drugs, unnary, 49-
50
m evaluahon of dosage
forms, 80-82
influence of moisture on per-
cutaneous absorption of
saLcylates, 206-207
as measurement of absoip
tion, 149
pH influence, 49
processes, 49
Expectorant, sedative, 395 396
Eye pads as surgical dressings,
453-454
Ft9 injecLon, 554 555
Fe“® preparations, 552
Fast Green FCF, resistance to
conditions influencing color
stabihty, 359
solubiLty, 358
structure, 357
Fats, mcompatibiLty, 324 326
P D & C, Blue, No 1, re-
sistance to conditions
influencing color sta
biLty, 359
solubiL^, 358
structure, 357
No 2, resistance to eondi
tions influencing color
stability, 359
solubiLty, 358
structure, 357
Green, No 1, resistance to
conditions influencing
color stabihty, 359
soluhiL^, 358
structure, 356
No 2, resistance to condi-
tions influencing color
stability, 359
solubility, 358
structure. 356
No 3, resistance to condi-
tions influencing color
stability, 359
soIubHity, 358
structure, 357
Orange. No 1, resistance to
condiLoos influenang
color stability, 359
solubiLty, 358
structure, 354
No 2, resistance to coodi
tions influencing color
SUbibty. 359
solubility, 358
Structure, 354
568 Index
F. D i C.— ’{Continued)
Red, No 1, reusunce lo con-
ditions influencing color
stability, 359
solubiUty, 358
stnicture, 354
No 2, resistance to condi-
tions influenang color
stability, 359
solubility, 358
structure, 354
No 3. resistance to condi-
tions influencing color
stability, 359
solubility, 358
structure 355
No 4, resistance to condi-
tions influencing color
stability, 359
solubility, 358
structure. 354
No 32, resistance to condi
tions influencing color
stability, 359
solubility, 358
structure, 354
Yellow, No 1, resistance to
conditions influencing
color stability, 359
solubility, 358
structure, 357
No 2, resistance lo condi-
tions influencing color
stability, 359
solubility, 358
structure, 357
No 3, resistance to condi
lions influencing color
stability, 359
solubility. 358
structure, 354
No 4, resistance to condi
tions influencing color
liability, 359
solubility, 358
structure, 354
No 5, resistance to condi
tions influencing color
stability, 359
solubility, 358
structure. 354
No 6, resistance lo condi
tions influencing color
stability, 359
solubility, 358
structure, 354
Ferrous Iron. 304
FicL's law of diflusioD, 32
Finl Bid preparations in aerosols,
281
Flavoring, solutions, 163-165
Flocculation, vs cnbng. in phar-
maceutical suspensions, 179
panicle, 179
Flow characteristics, sanous ma-
tcnals, 183
Fluid measure, equivalents, 8
Fluorescein dyes, 355
Fluorescein sodium, sotubilily,
358
stnicture, 355
Fluorescein, soluble, structure.
355
structure. 361
5 Fluorouracil, active transport,
39
Folic acid, 375
Foot preparations, in aerosols,
282
Formaldehyde. 314 315
incompatabiliiy. 315
Formaldehyde hydrate, structure,
315
Formic acid, dissociation con
seam. 318
solubility. 317
Formulation factors, pharmaceu
lical. 69 76
Fouler s solution, 302
Franklin, Benjamin, quoted. 476
Frederick II of tiohenstaufen. 2
Freon, 260, 263
Freundlich adsorption isotherm,
51 52
Fned's Rule for calculaung dos
age. 17
Fuchsin, structure, 356
Fumane acid, dissociation coo
stont, 319
Galen 2. 213
Gallic acid, solubility, 321
Callotannic acid Set Tanmc acid
Gantruin See Sulflsoxizole
Gas flow detector for solid beta
emitting samples, 542, 543
Gastrointestinal agents. 397-398
Castromlestinal fluids, drug sla
biltty in, 62 63
GailroinCcstmal tract, drug ab-
sorption in, influences. 40-
42
emptying rate, effect on ab
sorption of drugs, 42-43
fluids, pH change induced. 41
mucosa, interaction of drugs
with components of. 43-44
Geiger Mueller sunrey meter,
portable. 538. 539
Gelatin J9I 192
glycennate^ as lupposiiory
base. 232 233
Genetron, 260. 264
Gentian violet stnicture. 356
Genatnc formula. 396-397
Germicides in aerosols, 28!
Globules, medicated, use in
homeopathy, 389
size in emulsions, 189
Glonoin, structure. 327
Gloves, rubber, 423-424
/l-Glucuronidasc, 47
Glucuromdes, formation, 48
Glycerol, structure, 327
Glyceryl Monostearate S E., 197
Glyceryl tnacetate, solubility,
326
Glyceryl Innitrate. structure, 327
Glyceryl tnoleate-IWJ. 552 553
Glycine, 47
Gtycol(s). esters, 197
polyethylene, as compressed
gas aerosol, 250
as suppository bases, 233
234
salicylate, influence of mois
lure on percutaneous ab-
sorpuon rate, unnary secre
tion data, 206, 207
Glycosides, 363-364
solubility, 364
incompatibility. 364
Olycynhiza 164
Gold'#', decay table. 529, 530
Cradumet tablets, 145
Granulations effervescent, prep
oration 103
Granule, coaling See Solids, as
dosage form coattog
Gnseoiulvin, 50, 56, 57
serum levels, effects of differ-
ent types of food intake, 79
side-effects, 78
CuBiacol, tiruelure 328
Cuanatol Hydrochlonde See
Chloroguanide hydrochlonde
Guanidines, structure, 338
Guinea Green, resistance lo con-
ditions influencing color sta-
bility, 359
solubility 358
stnicture 356
Gums 307
Hahnemann, Dr, Law of Simi-
lars 387
Half life, biologic, 44-49
intenubjcct variation, 48
sulfa drugs 45-46
Hamllion, Joseph G, 525
Hand filling machine for jars,
lubes and other containers,
491. 492
Hamson Narcotic Act, 29, 494-
496, 498-499
classes of narcotics 499
multipic-dose via] problem,
499
procedure, in case of loss and
theft. 498
Index 569
Hamson Narcotic Act,
procedure — (Continued)
m case of waste, destruction
and contamination, 496,
498
registration, 494-496
storage of narcotics, 499
violations, questions on law
and regulations, 498-499
Heat of fusion, 151, 153
Heating pads, electnc, 430-432
Hectonte, 187
Henderson Hasselbach equation,
55, 156
Hepann, 56, 66
n Heptaldehyde, solubility, 313
Heptane, boiling point, 328
solubility, 328
Heptyl alcohol, solubili^, 313,
316, 328
n Heptyl alcohol, solubility, 330
n Heptylamine, solubility, 330
Hexamelhomum cblonde, struc-
ture, 343
HexamethylparaosaniUne chlo-
ride structure, 356
Hexameton Cblonde See Hexa
methonium chlonde
Hexane, boiling point, 328
solubility, 328
Hexyl alcohol, solubibty, 313,
316. 328
n Hexyl alcohol, solubility, 330
n Hexylaimne. solubility, 330
Hexylresorcinol, mcooipatibiluy,
312
soIubiLty, 312
Hind-Goyan buffer, 174
Hippocrates, 1, 2, 387
Hippunc acid, 50
Histadyl See Thenylpyiamine
hydrochlonde
Histamine, solubili^, 341
Histamine phosphate, structure,
337
History of prescnptions, 1 3
HLB system See Hydrophile
lipophile balance system
Hobart Mixer, 219
Holocaine See Pbenacaine by
drochlonde
Homatropine hydrobronude, sol
ubility, 341
structure, 335
Homeopathy, concept of, 387
development of profession, 387
dosage forms, preparation, 388
education m, 387
organizaUons, 387-388
pharmaceutical services to,
387 389
pracUtioners, 388
present status in Umted States,
387 388
Homogeoizer, basd, 181
Homologs, absorption, from gas
trointestinal tract, 69
Hose, elastic, 427-428
Hospital phannacy, 476 523
automation. 522 523
adfflimstratiOQ of drugs, 522
523
dispensing of drugs, 522
charges for drags, 512
containers for medication, 507-
S09
ward issue and prescription,
standardization, 507
definition. 476
dispensing, inpauent, 507
emergenqr and antidotal drugs
cabinet. 51I-SI2
equipment 488-492
safety, 491
first in Colofua] America, 477
formulary, five point statement
of operation for system,
484-485
purposes and goals, 482,
484-485
history, 476 477
mspeaioD of nursing station
medteauou units, 509, 511
lavestigalional drugs, use in
hospitals 500-501
labels, 507 509
phannacy, 508 509
prescnptioo, 507
warning stnp, 507 508
laws and regulations, 491 500
narcotics and other records
in hospitals See Narcot-
ics, m hospitals, laws and
regulations
management responsibilities,
513
organization, 479. 480
outpatient department, 511
personnel. 485-486
Donprofessional, 486
physical facilities 486-490
complete department, 486
space requirements and lay-
out. 486-487, 490
poliaes, 480-481
Phannacy and Therapeutics
Committee. 481-483
prepackaging, 504 506
purchasing of drugs, 512 S13
reports, quarterly and annual,
for costs and workloads,
516 521
requisiUoouig of drugs, *7iouse
orders,” 509, 510
residencies 523
responsibilities and duties of
pfaannaast, 478-480
to admuustratioo. 478
Hospital pharmacy, responsibili-
ties and duties of pharmacist —
(Continued)
to clinicians 478
to the department. 479-480
to nursing profession and
paramedical groups, 478
479
safety practices, 501 502
statistics, vital. United States,
478
stenle items, central supply,
513
stock, control, and storeroom
arrangement, 514 515
inventory, perpetual records,
515 516
policy, 514
volume compounding 502 504
Household measures, 8
equivalents, 8
Hycodac See Dihydrocodeinone
HydraUon, energy of, definition,
293
as factor m compounding tech
nics, 110 III
sulfates of alkaline earth met
als, 295
Hydrazobenzene, structure, 360
Hydrocarbons, fluonnated See
Aerosols, propellants, lioue-
fied gas, fluonnated hydro-
ear boos
saturated, 305 306
incompatibility, 305-306
solubility, 305
Hydrocolloids, animal, 185
denvatives, cellulose, 185-187
modified plant, 185 187
ionic behavior, 188
plant, 184 I8S
natural, 184 185
preservation, 185
pseudoplastic flow, 183
Hydrocortisone, 47
Hydrocortone Phosphate Injec
tion, 175
Hydrogen bonding, 154
Hydrolysis, as cause of drug de
composition, 161
rate, propellants of aerosob,
269
HydrophUe Iipophile balance
(HLB) system. 195 197
use. 195 197
vaJoes, 0/lV emulsions of com
mon mgredients, 195
selected emulsifying agents
196
Hydroxy polycarboxyhc adds,
320-321
mcompatibiLty, 320 321
acids, solubility, 320
5 Hydroxy tryptamme, 50
570 Index
Hfgroscopiclty. 112
Hypnotics, in dentistry, 385
in podiatry, 392
Hyoscine. Set Scopolamine
Hypospray, 448
!•** preparations, 552 553
Ice ba;:s or caps, 4t2>413
tdeniificailon Guide for Solid
Dosage Forms. identificaUon of
tablets, 11M17
Ileostomy vs colostomy, basic
differences, 415
Ilotycio. See Erythromycin
Imidazoles, structures, 337
Incofflpatibilitydes), chemical,
291 292
dcfiniuon, 290
iDorgiruc compounds See
Compounds, ino^anie, tn
eompatibniiies
pharmaceutical, 291
physical, 291
therapeutic. 290-291
types, 290
Index Medleus Information on
dosage forms, 87
Indigo Oirmlae, resistance to
conditions mfluenciog color
stability, 359
structure, 357
lodigoid dyes, 357
Incompatibility, 363
Indoles, structures, 336-337
Infrared rays generators, 465-466
faeatiog action, 464-465
therapeutic uses. 466
Inhalants, pharmaceutical. In
aerosols 282-283
Inp^tion, Ca*f, 552
chlormcrodrln Hg****, 532
Cr^t normal human serum at
bumin. 535
rt«. 554 555
Kr«5. 534
nidioiodinated rose Bengal, 553
ndioiodinated p loluldioe poly
vinylpyrrobdone (H**), 534
S»». 353
sodium iodohlppurate
353-554
tntiated water (H|0), 334
Inositol. 375
Inscnpuon. 4
InsulTlations. powders for, 100
Insufflators, pawder, 439, 440
Insulin, syringes, 442
Intentate Commerce Commis-
sion, flame extension test for
aerosols, 286
Intracaine hydrochloride, solubil
ity. 341
structure, 334
Inulin, 66
Todetkon. stroctare. 355
Iodoform, 67
lodophthalein sodium, solubility,
358
structure, 355
lon-dipote interactions, salts in
water. 155
lon-excbange resins evaluation
by toxiaty tests in animals.
149
as method of sustained release
of pharmaceuticals, 14S 146
Ionic types, average t values, 168
lomzaiioft chamber survey meter,
portable 539 540
lophenoxic add, 52. 53
Iron hydroxides, 303 304
incompatibilities, 303 304
salts. 303 301
Irish hfoas See Chondrus
Isoamytbydrocupreine, structure,
335
Isocarboxazid, SO
Isomylhydfocuprcine See Eucu
pm
Isomazid, 48
Isonipecame See Mepcndinc hy
drochlonde
Isoproterenol, and epinephrine
aerosol suspensions, particle
size, 284
luspension. effect of intertial
pressure on particle size dis
tnbuuon emitted, 284
Isoqumolines. strtietures 335 336
Isocron 260
Jetene as oleaginous base, 211
Joint Commission on Accredita-
tion of Hospitals, 477, 523
Journal of ihe American Medical
Association, Information on
dosage forms, 85 86
Journal of FharmaeeuUeal Jef-
enees inlormBtion on dosage
forms, 85
Kanamycio, 48
Ktraya, 183
Keesom forces, 133 134
Keratin, 204 205
Keratolytic agents, 202
KmtopIastiC agents, 202
Ketones, chemistry, 316>317
incompatibilities. 316
solubtli^, 316-317
^4-3 Ketostcroids, 51
Ketostix reagnt stnp, 430
Key to Pharmaceutical and 5fe-
dictnel Chemtstrj JJleratttre, A,
information on dosage forms,
87
Kr** injection, 554
Labels and labeling, “excuse la-
bel.'* 5-6
machine for prepackaging oper-
ations, 491, 492
narcotics, 27
ointments, 221-222
presenpuon, 22
Lactofiavin 376 377
Lanolin, anhydrous, as absorption
base, 192, 212 213
Lard, as oleaginous base, 209
Latin, pharmaceutical, 9 14
useful words and phrases with
abbreviations and meanings,
10 14
Launc acid solubility, 317
Laulh’s violet, structure. 356
Law of Cure, attributed to Hip-
pocrates, 387
Law of Similars 3B7
Leaching as process of steady dis-
solution and removal of drug
from insoluble, intact matnx,
144 145
Lead, acetate, structure, 318
compounds solubilities, 301
Incompatibilities, 300-302
oteale, structure, 318
salts 301-302
Legal aspects of pharmacy, 26 30
common law, 28
criminal liability for injunes of
fatality from prescriptions
containing ove^osages of
drugs 17
Federal Food Drug and Cos-
metic Act of 1938, 24, 26
Federal Narcotic Act, 28
Federal Narcotic law and
Regulations, 2627
Hamson Narcotic Act Set
Harrison Narcotic Act
narcotic prescriptions, 26-26
Statiiia rive Leges. 2
Leuco base, stTUCture, 362
Lcuco form, structure, 360
Leucopararosanilinc structure,
362
Licensure, medical, pharmaeeull
cal services to, 382 383
Udocaine, 146
Light Green SF Yellowish, re
sistance to conditions influ
encing Color stability, 359
solubiliiy, 358
structure 356
Lipid solubili^ of drugs, 54 56
Liquids, absorption from gastro-
intestinal tract, 69 71
as dosage form, 69 71
containing insoluble matter,
178 199
caking vs. flocculation,
179
Index 571
Liquids, as dosage form, cod-
taimng insoluble matter —
{Continued}
properties, I78-179
suspensions See Suspen-
sions
dispenions, liquid m liquid
See Emulsions
incorporation with powder, 109
Lithium salts, 293-294
solubility, 293
London forces, 154, 155
Lozenges, as dosage form, 138-
139
Lubncant, addition to compressed
tablets, 120
effect on dissolution of drugs,
75
MacEachent, Malcolm T„
quoted, 514
Magenta, structure, 356
Magnesium 294 296
oxide, 295 296
salts, 294, 295
sulfate, 50, 294 295
Iifalachite Green, solubility, 358
structure, 356
Maleic acid, dissociation constant,
319
Mallopheoe 5eePyndium
Mannitol, 66
hexanitrate, structure, 327
Masks, surgical, 460-46 1
Mayer’s reagent, 299
Measuring, Aliquot method, 20-
22
KlechoIyL See Methachohne chlo-
nde
Medical Letter on Drugt and
Therapeutics, The, infonnation
on dosage forms, 86
Medicine, pharmaceutical serv-
ices to, 382 383
practice of, phannaceutical
services to, 383
Medicme dropper, 420-421
Medihaler, 285
Medules as sustained release
pharmaceutical form, 142, 143
Melting point, depression, as fac-
tor in compounding technics,
113 115
Membranes, cutaneous, pennissi
ble concentrations of drugs for
application to, 291
Menadione, 373 374
sodium bisulfite, 373
M»acnne Hydrochlonde. See
Qumacnne hydrochlonde
Mependine hydrochlonde, solu
bility, 340
structure, 337
use m dentistry, 395
Merbromin, solubility, 358
structure, 355, 357
Mercodeinone. See Dihydroco-
deinone
Mcrcunc iodide, 299
Mercunc salts, 297-299
Mercurochrome See Merbroimn
Mercurous chloride, 298, 299
Mercury, 293 299
incompatibihtics, 298 299
Mesantom. See Pbeoantoin
MesomositoL 375
Methachohne chlonde, solubility,
341
structure, 343
Methadon. structure, 333
Methadone hydrochlonde, solu-
bility, 341
Methamphetamiiie, solubihty, 340
structure, 333, 347
Methantbelioe bromide, structure,
343
Methmm Chlonde See Hexame
thomum chlonde
Methocei, 308 309
Methyl acetate, solubility, 324
Methyl prednisotone, 61
Methyl sahcylate. loffuence of
moisture on percutaneous ab-
sorption rale, unoary secretion
data, 206, 207
Methyl violet, structure, 356
Methylamme, dissociation con-
stant. 330
Methylaffiinoetbanolcatecbol,
structure, 333
Methyl n butyl ether, boiling
point, 328
solubility, 328
Methylcellulose, 70, 185 186, 191,
308 309
Methyldibydromoiphmone bydio-
chlonde, structure. 336
Methylene Blue, solubility, 358
structure, 356, 362
Melhylparaben, mcmnpatibihty,
326
Metbylrosamlme chlonde, solubil-
ity, 358
structure, 356, 363
Methylthioouie chlonde, struc-
ture, 356
Metopon Hydrochlonde. See
M^yldthydromorphiDone
hydrochlonde
Mctnc system, 4 7
equivalents, 8
Metycaine See Pipcrocaine hy-
drochlonde
Micelles, 157
drug binding, 67
formation, 67
Micronizer, Sturfevant. 180
Minimum Standard for Pharma
cies m Hospitab of the Amen
can Society of Hospital Pbar
macists, 478, 480-482, 485-487
Mixing, by geometnc dilution, 97
Mixture, eutectic, 72
Kfoleskin, 454
Monocaine hydrochlonde. solu
bility, 341
structure, 334
Monocarboxyhc aads (fatty acid
senes), chemistry, 317-318
dissociation constants, 318
incompatibility, 318 320
solubility, 317
Morgan, John. 2
&forphme, solubility, 341
sulfate, structure, 335
Muscle relaxant, 398
Mycifradm SeeNeomycm
Myrutic acid, 319
solubihty, 317
Naepaine Hydrochlonde See
Amylsine hydrochlonde
Nalline Hydrochlonde. See Nal-
orphine hydrochlonde
Nalorphine hydrochlonde, solu-
bility, 341
structure, 336
Naphazolme hydrochoinde, solu-
bility, 341
stnicturc, 337
Napbtbol Yellow, resistance to
coDdiUoDS influeociag color sta-
bility, 359
Napbthol Yellow S, solubility,
358
structure, 357
Narcotics, classification of. 27-28
in hospitals, laws and regula-
uons, 492-497
Federal food and drug
code and regulations,
500
Harmon Narcotic Act,
494-496. 498-499
prescnptions, 26-28
U S Bureau of, 27
National Board of Dental Exam-
mers, 383
Nationd Board of Medical Exam-
iners. 383
Nebulizers, 437-440
Needles, hypodermic, 444-448
construction, 444, 445
disposable, 446
insulin, 448-449
packaging, 446
selection, 445-446
sizes, 445
sources, 446
use and maintenance, 446-
447
wires, 446
NembutaL See Pentobarbital so-
dium
Neomyan. 367
Neo-SUvol, 365
572 Index
NeoiUgrame, 147
Ncmtifminc bromule, solubilit),
341
stnKturc, 343
NeosUpmme mcthylsulfatc, solu
bihty. 341
structurE, 343
Neoijnephnne See Phen)leph
nnc hjdrochlonde
Neo-Sjncchnne Injection, 175
Neo-Vadnn, 175
Ncthamine hydrochloride, solu
hiJiJy, 341
structure, 333
and Nonofflelal Drugs in
formation on dosage forms. 86
N F VIII. Latin titles, listed
second to English, 9
XI. Latin titles omitted, 9
Niacin See NicoUme acid
Nicotinamide 373 376
Nicotine solubility. 341
structure, 334
Nicotinic acid, 375 376
Nipple shields, 424
Nitnie esters, incompatibility,
326-327
Nitfo djes, 357
meompatibilit}. 363
Nitrogen as propellant in aero-
sols. 271
Nitroglycenn 63
structure, 327
Nitrosoanupyrine structure 327
o-Nitrosophenof structure, 327
p Niirosophenol. structure, 327
Nitrous oxide as propellant in
aerosols 271
n Nonyl alcohol solubility, 330
n Nonylamine solubiliW, 330
Novobiocin 62. 96, 36‘/-368
Novocain. Jee Procaine h}dro
chloride
Noyes Whitney law, 56
n Octyl alcohol, solubility, 330
R-Oct)lamtne, solubility, 330
Oil Red XO, resistance to condi
tjons innuenemg color sta-
bility, 359
solubility, 358
structure, 354
Oils, fixed, incompatibility, 324-
326
vegetable, as oleaginous base,
209
Ointmcnt(s), bases, general indi
cations for, 204
classification, 203 204
definition, 201
effect on slin, general factors
affecting absorption,
205 209
amount of inunction, 20S
area of application, 208
Ointment(s), effect on skin —
(Conrmueif)
concentration of medica-
meat in schicle. 208
209
condition of skin 209
eovenng or bandapng
over vehicle. 208
frequency of application
and length of contact
Ume. 209
solubility of drug tn ve
hicJe. 208
hydration, 204-205
labeling, 221-222
ophthalmic. 217-218
I^kapng. 221
preparation fusion. 220 221
mechanical incorporation,
218 220
storage. 221
water number, 213 214
Oleandomycin 368
OIcic acid incompatibilily 318
Oleic acid Ii»«, 552-553
Ophthalmic preparation. 398
Orange I, resistance to condiuons
inffueoeing color stability,
solubility 358
stroctufc, 354
Orange SS resistance to condi
tiotts inffueoeing color sta
bifity, 359
solubility, 358
slfucture, 354
Ortal sodium, solubib^, 349
structure, 348
Orthohydroxybeitzoic acid. 322
Osmotic pressure, dcffnition, 167
ophthalmic solutioos, 16^169.
173
Osteopathy, concept. 389
education and training, 390
pharmaceutical services to,
389 391
prescnbiog practices 390 391
jinncjples. 389-390
in United Sutes. 390
Oxalic acid, dissoaation constant,
319
solubility, 319
Oxyqumolme. solubility. 341
structure. 335
Oxylctracyclmc. 370
PABA See p-AmioobcnzoIc acid
solubility, 319
Packaging, ototmeatt, 221
solutions, 16S
lablrti. 127
Palmitic acnf. 3t9
solubility, 317
Pamaquine, naphthoate, solubil-
ity. 341
structure, 335
Pantothenic acid, 376
Papaverine, solubility, 341
structure, 335
Parabens, 162
Paraform See Paraformaldehyde
Paraformaldehyde, 315
Paraldehyde, incompatibibties,
314
structure, 314
PararosaniJine, stnicture, 362
Parednne, hydrobromide, solubil
«ty. 341
structure. 333
Particles, interaction in suspen
sion. 179
pulsenution methods. 180
reduction of size, equipment,
181-182
size in relation to pharmaco-
logic action, 179 180
Pastes, 222 223
Pectin. 190-191
Pelleiienne, solubility, 341
structures, 334
Penicillin. 146, 368 369
V. 62
serum levels when dispensed
as free acid or as potss
Slum salt, S8 59
tablet form disintegration
time 74
Pentaerythntol teiranitrate, struc-
ture 327
Pentane, boiling point, 328
solubility 328
Pentobarbital sodium, solubility,
349
structure, 348
Peniothal Sodium See Thiopen
tal sodium
Pcntraie, structure, 327
Pethidine See Meperidine hydro-
chloride
Petrolatum, hydrophilic, as ab-
sotpiion base 212
jelly, as oleaginous base, 209-
210
as oleaginous base, 209 210
rose water ointment, as absorp-
tion base, 213
Pfizer Tester, hardness of cap-
sules and tablets. 128
pH. changes in acid ionizatioo in
f ill environments of gastro-
ntestmal tract, 40-41
effect, on hydrolysis, 160
on solubility, 156 157
gastrointestinal fluids, changes
induced in, 41
Influence on urinary drug ex-
cretion rate, 49
Index 573
pH — (Continued)
methods of changing in diffu-
sion layer, 57-58
of precipitation, calculation,
156-157
solutions, ophthalmic, 173 174
Phanodom, solubility, 349
structure, 348
Pharmacopolot 1
Phemerol Chlonde See Benze
tbonium chlonde
Phenacame hydrochlonde, solu
bility, 341
structure, 338
Phenantoin, structure, 351
Phenazone See Antipynne
Phenelzme, 50
Phcniprazine 50
Phenobarbital, solubility, 349
structure, 348
PfaenoUs), 310 313
acidity, cause of, 310-311
bactencidal activity, effect of
surface active agents, 67
chemistry, 311 313
dissociation constants 311
incompatibility. 311
solubility, 310, 311
structure 327
Phenol Red, structure, 355
Fhenolphthalein, solubility, 358
structure, 353. 361
Pheoolsulfoopbthalem. solubility,
353
structure 355
PhenoItetrachloropbtbaleiQ, solu
bihty, 358
structure 355
Phenolhiazine. 57
solubility, 358
structure, 338, 356
Phenyl salicylate, incompatibil
ity, 325
Phenylalkylamines, structures,
332 333
Phenylbutazone, 52
Phenylephrine hjdrochlonde, sol-
ubility, 341
structure, 333
Phenylindanedione, blood level
data, 37
Phenylpropanolamine hydrochlo-
nde, solubility, 341
structure 333
3 Phenyl 1,2,4 tnazole, SI
Phenyloin, soluble See Diphenyl-
hydantom sodium
Phethenylate sodium, structure,
351
Phthalem dyes 355 356
incompatibility, 360-361
Phthalimide, structure, 330
Phthalysulfathiazole, structure,
346
Physostigmme, salicylate, stnic-
ture, 336
solubility, 341
Picnc aad, 312 313
P I D , 175
Pigmentam, 2
Pill, coating See Solids, as dosage
form, coating
as dosage form. 138
Pilocarpine, nitrate, structure,
337
solubility, 341
Pmoiytosis, 40
Pipendine, dissociation constant,
330
stnicturea, 337-338
Pipendine pyrrobdines. condensed
(ttoptne), stnictures. 334 335
Piperocaine hydrochlonde, solu
bility, 341
structure, 337
Placebos, use tn drug expen
ments, 77 78
Plasma protein binding of drugs,
51 54. 65
Plaimochin See Pamaquine
napbtboate
Plasters, 223 224
Plasubase as oleaginous base, 21 1
Pliny, 2
Podiatry (chiropody), 391-393
drugs used to. forms and
sources, 391
education and pracuce, 391
pharmaceuucal services to,
39( 393
Polanzabibty, molecular, 153
154
Polycarboxylic acids, dissociation
constants, 319
Polyethylene glycol, 400 mono
stearate, I97
ointment, 216
Polymorphism, chemotherapeutic
implications. 60 62
Polymorphs, metastable, 60-61
preparation of, 60
solubility, 152 153
Polymyxin, 369 370
Polyoxyroethylene, structure, 315
Polyvinylpyrrolidone, 65
Ponceau SX, resistance to con
ditions infloenang color sta
bihty, 359
solubili^, 358
stnicture, 354
Ponceau 3R, resistance to condi
tions infiuencing color stabil
ity, 359
solubility, 358
structure, 354
Ponlocatne See Tetracaine hy-
drochlonde
Potassium, acetate 102
arsemte soltUMm, 302
Potassium — (Continued)
salts, 293 294
solubility, 293
Poultices, 224
Powders, 97-102
advantages. 97 98
bulk, 98 99
douche, 100
divided, 100-102
dusting, 99 100
insoluble, incorporation Into
suppositones 240
insufflations, 100
medicated, use in homeopathy,
389
mixing procedure, 98
papers, directions for folding,
101
Precipitation, pH of occurrence,
calculation, 156-157
Predisone, 71
Prednisolone, 71
Preservatives, for emulsions, 198-
199
ophthalmic, 165 166
Prcscnpfion(s), 1 30
accessones and related items,
400-170
atomizers, 434-437
canes 464
crutches, 461-464
diabetic supplies, 448-450
elastic supports See Elastic
supports
electric heating pads, 430
432
nebulizers, 437-440
needles hypodermic See
Needles, hypodermic
powder insu^tors, 439, 440
rubber See Rubber acces-
sones
sales in pharmacies, 401
sickroom utensils, 429-430
surgical dressings See Dress
mgs, surgical
syringes, hypodermic See
Synnges, hypodermic
thermometers See Ther
mometers
vaporizer humidifien, 432-
434
checking, 22 23
compound, 4, 5
compounding. 18 22
accuracy m, 19
weighing, 19 22
daily work sheet, 23 24
dehnitioo, 3
dispensing, 16-24
filing, 24
history, 1 3
homeopathic. 389
information recorded on, 23 24
574 (ncfex
Prwcnption(j) — (Continued)
UbcliBg. 22
of narcotics, 27
ownership. 28 30
pans, 3 7
pilot sheet, 15 16
procedure, 9, 15 26
processing, 15 16
reading, 16-17
refills, 24 26
regulations for barbiturates,
etc . 24 25
safety, check for, 17 18
dosage form IS
frequency of administration
IS
by telephone, 16
tolerance for drugs. 18, 19
S ical, 3 7
Icleof IS
Pnvine H>droehlonde JeeNaph
azolme hydrochloride
Pro-Daaihme See Propantheline
bromide
Probenead, 50, 323
Procaine hydrochloride, solubil
tty, 341
structure, 333
Prefiavine dihydrochlonde, solu
bility 358
structure. 353, 360
ProIIavine sulfate solubility 358
structure, 353
Premaane. structure 338
Promethasne, structure. 338
Proeadnne Hydrochloride See
Phenylpropanolamine faydro-
chlonde
Propane, boiling point, 328
solubility, 328
Propanihefine bromide, structure,
343
Propellant 12. 260-268
Propionaldehyde. solubility, 313
Propiowe and, dissociation eon
slant. 318
solubility 317
Propyl acetate. 324
Propyl alcohol solubility, 313,
316, 324 328
n Propyl alcohol, solubility, 330
Propylamine solubility, 330
Propylparaben, mcompatlbriity,
326
Prostigmine Bromide See Neo-
stigmine bromide
Prostigmine Methylsulfate See
Neostigmine methylsulfate
Protcctives of sUn, 203
Pryidines structures, 334
Pteroylglutamic acid, 375
Punnes, structures 338
Pyramidon See Aminopynne
Pyrazinamldc, 48
Pyraiolcs structures, 337
Pyribcnzamine See Tnpcletma
mine hydrochloride
Pyndine pyrrolidines, structure,
334
l^ndium, sofobihty, 358
structure. 353
Pyndoxxne, 376
P^dylbenzy-dimethylethylene
diamine bydrochlonde, stiuc
lure, 332
Quartemary ammonium com
pounds, as ophthalmic preserv
Btives, 166
Quinacnne hydrochloride solu
bility, 358
structure. 353
(juiDidine, solobibty, 34}
sulfate, structure, 335
Quinine solubility. 341
structure, 335
Quinolines structures. 335
Quinone monoxime structure 327
Radiant heating local, technic,
466-467
Radioactive isotopes as tracers In
ammal studies, evaluation of
sustained release of drugs. 149
Radioactivity, catcutatioos, 538
539
dosimetty, beta 538
gamma 538 539
decay, 528 531
alpha particle, 530
beta particle 530
modes, 530-531
orbital electron capture, 531
positron, 530-531
detection instruments, 539 548
Ionization chamber. 542 543
laboratocy. 541 548
monitonng personnel 540-
541
recions of response, 531, 542
scintillation 543 548
liquid detecton 545 548
solid detectors, 543 545
survey, 538 540
protection from 533 538
acceptable nsk 537 538
maximum permissible ex
posure, 534
methods 535 537
chemical agents 537
Internal b^rds 535 537
radiochromatogram scanner
with count rate meter and
rectilinear recorder, 548,
549
radioisotope gloved box with
aseptic transfer in progress,
549
relative biologic effectiveness
and type of radiation 533
Radioactivity — (Continued)
remote pipetting device, for
beta-emitting and low-
activity gamma<mitling
radionuclides, 547, 549
for bulk gamma-emitUng
radioisotopes, 546. 548
types. 526-528
artificial, 526 528
neutron induced, 527, 528
reactions, charged particle,
527-528
photon induced, 528
natural. 526
units, 531 533
dosage. 532 533
radiation absorbed dose,
532 533
roentgen, 532
roentgen equivalent man,
or rem, 533
quanti^, nine, 532
specific activity, 532
Radioiodmated rose Bengal in
jection, 553
Radioiodmated p-toluidme poly-
vinylpyrrebdone (P*i) injec-
tion, 554
Radiophamiaceutieals, 525 557
dosage forms 549 550
formulation and dispeasing
procedures, 550-551
packaging, 550 551
history, 525
laws and regulations regarding
procurement and use of
radionuclides, 556-557
philosophy of a service, 525
526
radioactivity See Radioactivity
use of products, 551 555
in diagnosis, SS2 554
in research SS4 556
Raoults Law. 151, I67-I68 263
Rate equations, reactions la soiu
tioo, 159 160
Remingtons Practice of Pharm-
acy, information on dosage
forms 86
Reserpine, 49
solubility, 341
structure, 336
Resins 364 365
incompatibility, 365
solubility, 364 36S
RtsorciQol. Incompatibility, 312
monoacctate. Incompatibility,
325
solubility, 312
Resorcinolpbthalein Sodium,
structure, 335
RMzotomoi, 1
Riboflavin, 65. 376377
intestinal absorption. 42
Index 575
Riboflavin — (Continued)
polymorphic forms, 60-61
Roberts, Jonathan, as fint hos
pita] pharmacist in Colomal
Amenca, 476
Roentgenography, m vivo, for
evaluation of release from en
capsulated pellets, 149
Rosaniline, chloride, structure,
356
dyes, 356 357
solu^hty, 358
Rose water omtment as absorp
Uon base, 213
Rubber accessones, 407-426
mandrel goods, 421-426
catheters See Catheters
cervical caps, 426
condoms, 424-425
contraceptive agents, 426
diaphragms, vaginal, 425-
426
finger cots, 424
gloves 423-424
nipple shields, 424
tubes See Tubes
tubing 42M22
manufacture, 408
molded goods. 409-421
enterostomy outfits, 414418
ice bags or caps, 412413
invalid cushions. 413414
syringes, 409412
huro. 418421
unoals, 414
water bottles, 409410
properties of rubber, 407408
sheeting goods, 408409
S3* injection, 555
Sal-ethyl carbonate solubility,
327 328
structure, 328
Sa\icy\at«, mfrotiKt cfi mmStme
on percutaneous absorption
rate, unnary secretion data
206, 207
use in dentistry, 385
Saheyhe acid 41. 4647, 49
dissociation constant, 322
dissoluuon rate, effect of lu>
bneant on, 75
incompatibility, 322
solubility, 321, 322
structure, 321
Salol, incompatibility, 325
Salol-camphoT mixture, phase dia-
gram. 113
Salts, dissolution in water, ion-
dipole interactions, 155
solubility in water, 292
Sandoptal, solubility, 349
structure, 348
Scarlet Red, solubility. 358
structure, 353, 360
Scarlet Red Medicinal See Scar
let Red
Scarlet Red Sulfonate, solubihty,
358
structure, 353
Scopolamine hydirobroraide, struc
ture. 335
solubility, 341, 342
Seconal sodium, solubili^, 349
structure, 348
Sedatives, in dentistry, 386
m podiatry, 391
Semisohds, 201-224
bases, absorption, 212 214
lanolin, anhydrous, 212
213
ointment, rose water, 213
petrolatum, 213
petrolatum, hydrophilic,
212
specialty (anhydrous and
hydrous), 214
water number. 213 214
emulsion, 214 216
speaalcy, 216
oleaginoos, 209 212
lard, 209
petrolatum (petroleum
jelly), 209-210
piastibase (Jelene), 21]
silicones, 211-212
spectalues coniainiog $ih-
cooes and sibcates, 212
vegetable oils, 209
white ointment, 210-211
yellow ointment, 210 211
water soluble, 216-217
cerates, 222
creams, 222
effects of local appbcation, 202
203
factors influencing selection of
type of preparation, 201
ovmmenVs See Om’uncma
pastes. 222 223
plastcn, 223 224
poultices. 224
Seplasarn, 2
Serenium, solubib^, 358
structure, 353
Seromyan See Cycloserine
Serpasi! Lijection, 175
Serum protein bmdiog, sulfona
mides, 52 53
Sickroom utensils, 429430
bedpans, 429430
care of bedridden paUenta, 430
douche pans, 430
kidney basins, 430
unnals, 430
Side-effects of drugs, tn evalua-
tion of dosage forms, 82 83
Sihcones as oleaginous base, 2II-
212
Silver protem preparations, 365
Silvol, 365
Skin, effect of ointments See
Ointments, effect on skin
Soaps, alkali (monovalent), 193
as emulsifying agents, 193 194
metallic (divalent), 193 194
of organic amines, 194
Sodium acetate, structure, 318
Sodium acetylsahcylate, structure,
323
Sodium alginate, 308
Sodium bicarbonate, 49
Sodium bromide. 111
Sodium carboxymethylcellulose
(CMC), 186, 191
Sodium chloride, equivalents of
drugs, not usually avail-
able in pure form, 171 172
usually available m pure
form, 169 171
Sodium citrate, structure, 321,
323
Sodium ethylenediamine tetraace
tate (EDTA), 66
Sodium formate, structure, 316
Sodium glucuronate, 47
Sodium Indigotindisulfooate, so
lubility, 358
structure, 357
Sodium iodide, 67
Sodium lodobippurate (I^^) m
jectioa, 553 554
Sodium lauryl sulfate, 59, 68, 75
Sodium oleate, structure, 318
Sodium para amuosahcylate, 37-
38
Sodium salicylate, 52
structure, 321, 328
Sodium salts, 293 294
solubihty, 293
Sodium sulfathiazole, structure,
346, 347
Sodium sulfocyanate, 102
So\i&s. capsules,
compounding technics, effects
of drug properties, 108
116
chemical reactivity, 115-
116
hydration, 110-111
hygroscopicity, 112 113
incorporation of liquids,
109
melting point depression,
113 115
potency, 108 109
volatili^, 109 110
IS dosage form, 71 76, 95 149
coating, I31 137
air sumension, 135
enteric 135 137
film, 133 134
press, 135
sugar, 132 133
coloring, 133
576 Index
Solids, Bt douge fonn, coatiof,
supr — {Continued)
finishing, 133
polishing, 133, 134
smoothing, 133
subcontins. 132 133
cvaJuauon. J27-131
disintegration, 129>I31
hardness, 128 129
organoleptic, 128
weight, accurate, 127 128
molded, 137.139
loaenges, 138-139
pills. 138
tablet triturates. 137 138
powders See Powders
sustained release pharma-
ceuiicals See Sustained
relexse pharmaceuticals
granules, 102-103
particle sue, 93-97
tablets See Tablets
water, of er)stallization. 111
of hygroseopieily, 112
Solubility, 130-137
alcohols 313, 316, 324, 328
monohjdroxy, 306
pol>hydrosy, 306 310
aldehydes, 313
alkaloids and chemically re
lated svRlhetic compounds
340 342
allanes, 328
aluminum compounds, 301
amines, 329 331
antibiotics, 366-371
aromatic carboxylic acids, 321
harbituratet, 349
chances of solvent, 133-136
dielectric constant, 133 136
dicarboxylic acids, 320
dissolution process, 130-133
heat of fusion, 131, 133
polymorphs, 134
Raoutl's Law, 151
van t HolT eq,uaUon 13 1
dyes 338
cfTect of pH. 136-157
Coulombs Law, 157
Henderson Hasselbach equa
tion. 136
precipitation from solution,
136
esters. 324
denved from inorganic acids,
326
etheri. 328. 329
general, Inorganic compounds.
292 293
glyrosides, 364
hydrocarbons, saturated, 305
hydroxides of alkaline earth
metals, comparison of hydra
tion energy with, 294
Solubility — (ContUuud)
hydroxy polycarboxylic acids,
320
interaction forces. 133-136
Coulomb^ Law, [53
dielectric constant of liquid,
154
dipole moments, 153-154
hydrogen bonds, 154
lon-dipole. 155
Keesom, 154 135
London. 154, 155
polanzability, 153. 154
ketones, 316
lead compounds. 301
monocarbotylic acids. 317
phenols, 310
polycarboxylic acids. 319
polyethylene glycols, 233
quarternary ammomum com-
pounds, 344
resins. 364
salts, of alkali metals 293
relationship of electrostatic
fields of canons to, 294
of alkaline earth metals, 294,
295
in water. 292
ainc and mercury, 297
silver protein preparations, 365
solubilization. 157
sulfates of alkaline earth metals,
295
sulfonamides. 346. 347
vitamins, fat soluble. 372 373
water soluble, 374 378
Solubilization process. 137
Solutionfs), advantages and dis
advantages, 150
aqueous, use in homeopathy,
388
coloring 163
dermilton, 130
dosage form. 130-176
flavoring. 163 165
isotowc. 169, ni
preparation by sodium chlo-
ride equivalent method,
169. 173
ophthalmic. 165 174
buffered. 174
pH. 173 174
osmotic pressure. 166-169,
173
preservatives. 165 166
stcnhty. 165
viKOiiiy Jilyustment, 174
osmotic pressure, prediction,
167-169
packaging 165
parenteral. 174
pharmaceutical. 174 176
solubility See Solidrility
special. 165-176
SoluUonfs) — (Continued)
stability, 157-163
autoxidation reactions, 161-
162
effect of temperature, [62
catalysts, 160 161
degradation, hydrolyuc, 161
by microHSrganisms, 162-
163
hydrolytic degradation. 161
rate ecjuation. reactions in
solution, 159
Solvates, 62
Solvent drag, 40
Soibitan esters. 197
Spansule(s), os sustained release
pharmaceutical form, 142-143
Sparine Injection, 175
Sparteine, solubility, 342
sulfate, structure, 334
Spint of nitrous ether, incompatl
bility, 326 327
Spironolactone, 72, 75
coadministraiion with polysor
bate, 68, 80
plasma levels after administra
tion in tablet form, 73
Spray-on protective films, in aero-
sols. 282
Stability of drugs, m gastrointes
linal fluids, 62 63
Sioitiia tweLtget, 2
Steanc acid. 319
solubility, 317
Siigmonene Bromide, See Bettzpy-
nnium bromide
Still, Andrew Taylor, 389
Sioke’s equation, 178 J79
Stokes Hardness Tester, tor cap-
sules and tablets, 128
Storage, ointments, 221
Stratum corneum, 202, 204
Streptomycin, 48, 370
Strong C^bb Tester, hardnen of
capsules and (ablets, 128
Strontium. 294 296
salts, 293
Strychnine, solubility, 342
sulfate, structure, 336
Sturtevant micronizer, 180
Subscription, 4
Succinic acid, dissociation con
Slant, 319
solubililv, 319
Suecini/mJe, structure, 330
Succinyliulfalhiazole, solubility,
347
structure, 346
Sugars, 306-307
incompatibility, 307
solubility, 30(^307
Sulfadiazine, 96
absorption rate, 56
serum levels after one 3 Gm^
dose, 97
Index 577
Sulfadiazine — (Conimued)
solubiUty, 347
structure, 345
Sulfadimethoxine, gastrointestinal
absorption, 71
Sulfaethidole. 49
Sulfaguaiudme, solubibty, 347
structure, 345
Sulfamerazine, solubility, 347
structure, 345
Sulfamethazine, structure, 345
Sulfamcthoxypyndazinem, solu-
bility, 347
Sulfamlamide, solubility, 347
structure, 345
2-SulfaniIamido 5 methoxy py
nmidme, 53
Sulfapyndioe, solubility, 347
structure, 345
Sulfasuxidioe, structure, 346
Sulfathahdme, structure, 346
Sulfathiazole, eutectic mixture, 72
solubility, 347
structure, 345, 346
Sulfinpyrazone, 53
Sulfisoxizole structure, 345
Sulfonamides, 345-347
biologic half life, 45
incompatibibly, 346 347
influence of EDTA on gastrom
testinal absorption, 66
plasma protein binding, 51 S3
In podiatry. 392 393
ratio of initial dose to main
tenaoce dose for maintaining
constant drug concentration,
45
solubility, 346, 347
m water, 152
Sunset Yellow FCF, resistance to
conditions influencing color
stability, 359
solubility, 358
structure, 354
Superscnption, 4
Supporters, athletic, 429
Suppositories, 226-240
bases 230 235
comparison of melting point
and liquefaction tune, 230
fatty substitutes, 232
gelatin, glycennated, 232 233
glycols, polyethylene, 233-
234
“hydrophilic, ** 234 235
theobroma oil (cocoa but-
ter). 23 1232
water soluble, 232 235
dispensing and compounding,
special procedures, 238-
240
dusting powders, 239
incorporation of insoluble
powders, 240
Suppositones, dispensing and
compounding — (Continued)
lowered melting tempera
ture, 239 240
lubrication, 239
plasQC molds, 239, 240
dosage, 228 229
manufacture methods, 235 240
companion, 238
compression, 236
fusion. 236 238
hand rothng, 235 236
molding. 237 240
shapes. 226 227
sizes 226 227
testing, 229 230
therapeutic uses, 228 229
Surface active agents (surfac
tants), 66 69
drug, 66-69
effect, on bactencidal activity
of phenols, 67
on drug absorption. 66-67
evaluation of effects, 68
Surfacaine solubility, 342
structure, 337
Surfactants S<e Surface active
agents
Suspensions. 178 188
“caking,” 179
dispensing, 199
dispersion subtltzers, 184 188
clays, 187-188
hydrocoHoids, animal, 185
lomc behavior, 188
plant 184 185
cellulose derivatives,
185 187
modified derivatives,
185 187
preservation, 185
synthetic. 188
packapng, 199
particles, reduction of size,
equipment, 181-182
preservation, 198 199
release of active ingredients,
70-71
rheologic properties. 183 184
stabiiimtioo, by increaung vis
cosity of dispersion me
dium, 182 183
thixotropic substances, 183
storage, 199
without suspending agents, 182
Suspensones, 428-429
Sustained release pharmaceuti
cals, 139 149
deflmtioo, 139
evaluation, 148 149
introduction into United States,
139
limitations, 147-148
methods and technics, chemi
cal, 146
Sustained release pharmaceuti
cals, methods and techmcs —
(Continued)
medical, 146-147
pharmaceutical. 141-146
controlled disintegration,
141-143
Medules 143
repeat action tablets,
141
Spansules, 142 143
erosion, f43 144
ion exchange resin, 145-
146
leaching, 144 145
Sweet spmt of niter, incompati
bihty, 326 327
Syntrcpan, solubility, 342
structure 334
Syrmge(s), 409-412
bulb, 418-421
breast pumps, 418, 420
for ear canal, 418-419
infant nasal aspirator, 418
420
medicine dropper, 420-421
rectal 419
urelbral, 420
vaginal douches, 418 419
disposable enema units, 411-
412
fountain 409412
folding or travel style, 412
byrodermic, 440445
Busber automatic injector,
442, 448
descnptiOQ, 440, 441
dispensing, 445
disposable, 442445
graduations, 440442
Hypospray, 448
insulin 442, 448449
jet injectors, 447, 448
special purpose, 442443
tuberculin, 442
use and maintenance, 446-
447
vaccine, 442-443
radioisotope, with plastic and
lead shields, 546
Tablet(s), advantages and disad-
vantages, 1 17-1 18
coating See Solids, as dosage
form, coating
compressed, 73 76. 116 127
abbreviations, 125
disintegration of drug 73-74
dispensing, 127
manufactunng methods, 118
124
precompression, 124
wet granulation, 119 124
binder, 120
color, 120
578 Index
T«btet(t), comprciscd, tnxnufic*
tnnnf rnethodi, net granula
tiojv— (Co«//nwfd)
cocnprnsioQ, I2I>124
desi^i engraved or em
boucd on surface, 1 20
difliculues encountered,
123
drying, 119, 120
lubncant and dtsinte-
grant, 120 121
weighing and mixing in
gredients, 119 121
types, 124 127
chewing 125
gastrointestinal tract. 124<
123
hypodermic administra
tion 126
miscellaneous 126 127
oral cavity, 125 126
subcutaneous admmistra
tjon, 126
vaginal. 126
counting machine, 491
disintegration, factors determin
mg 129 130
test, industnai apparatus. 131
U5P. 130-131
Identification 116 117
lubncanis, 75
repeal-action, technics of eb-
lajning controlled dismtegra
tion. 14] 143
sustained release S«€ Sus-
tained release phannaceuti
cals
triturates 137
uncoated, weight vanation tol
erances. 128
weight, accurate, P taler
ances I27-128
Tannic acid incompatibility, 324
sotubiluy. 321. 323 324
Tannin See Tannic acid
Tartanc acid dissociation con
stant 319
inrampatibiliiy, 320
solubiLty, 319
Tartraidne, resistance to condi
diuons influencing color sta-
bility, 359
solubility, 358
structure, 354
Taylor. A n,.226
Temperature, effect of degrada-
tion of stability of solutions,
162
Terramyctn See Osytetracycline
Test(s). disintegration of drug fn
tablets, 73 74
flame extension, for aerosols,
286
methods, objective vs lubyec
Lve, 7677
Test(s) — (Conrinued)
toxicity, in animals, for evalu
ation of ion-exchange resins,
149
weight, capsules and tablets,
VS P tolerances, 127-128
Tea Tape, 450
TestMtcroDe,7l
Tetraalbyl ammonium halide,
structure, 344
TetraalbylammoniuRi hydroxide,
struenire, 344
Tetrabromophenohulfoophlha
letn structure 356
Tetracaine hydrochloride solubil
ily, 342
structure 334
Tetracyclines, 370 371
compfexed snth cations, ab-
sorotion of. 66
effect of dissolution rate on
gastrointestinal absorption,
58
of serum on antibactenal ac
tivity, 53
excretion rate. 81
gastrointestinal absorption,
80 81
local Side-effects 38
plasma protein binding 51,53
54
Tetraeyo See Tetracydifle
Tetraethylammonium ehlonde,
solubility, 342
structure 343
Tetraiodophenolphthaleitt sodium
structure. 355
Tetramelhylthionine chloride,
structure, 356
Thenylene See Thcnylpyramine
hydrochloride
Thenylpyramine hydrochlonde,
soiubiUly, 342
structure, 332
Theobroma oil (cocoa butter) as
suppository bw, 231 232
Theobromine solubility. 342
structure 338
Theophylline, blood level data, 34
solubility, 342
structure, 338
Thermal analysis of dissolving
drug tablets. 76
Thermometer(s). clinical, 400-
407
accuracy. 403-404
basal. 405-406
body temperature. 400-402
broken in situ. 407
cuset and accetsorfes, 406-
407
charactcnstJCS 402-403
cleamnganddisinfeaing, 406
extremes, 401-402
manufacture of, 402-403
Thennometer(a), clinical — (Con-
tinned)
normal, ranges, 400-401
types, 402
use and maintenance, 404
405
Thiamine, 377-378
adsorption on diluents, 72
chlondc. 377-378
intestinal absorption 42
Thiantom Sodium SeePhethcnyl
ate sodium
Thiazine dyes, 356
incompatibility, 362 363
Thiochromc, 378
Thiodiphenylammc, structure, 356
Thiontne, solubility, 358
structure 356
Thiopental sodium, solubility, 349
structure 348
Thixotropy, 183
Thorazine See Chlorpromazmc
Thymol, incompatibility, 312
solubility, 312
Thyroxine, 48 50
Tin, incompatibilities, 300-302
use m homeopathy, 388
Tocopherois, 373
Tolbutamide effect of dissolution
rate on gastroiniestinal absorp-
tion and blood sugar lowcnng
activity, 58
Tofaquine, solubiMy, 342
structure, 335
Tragaeanth, 184 185, 190, 308
Tranquilizer(s), 398
we In dentistry, 386
Transcription, 4
Tmseniine. solubility, 342
structure 334
TnaccUn solubility, 326
Tnchloracetaldehyde. structure,
314
Trichloracetic acid 316
dissociation constant, 318
incompatibility, 319 320
solubility, 319
Tnchlorocthanol 316
Tneyciamo) svlIate,so)ubihty,3A4
Triethanolamine, solubility, 342
structures, 333
Tnethylaminc, dissociation con
slant 330
Tniodophenol, 67
Tniodoihyronine, 48, 50
L-Tniodothyronine l‘*t, 553
Tnmcthylamine, dissoclauon con
slant, 330
Trinitrophenol, 312 313
dissociation constants 311
Tripdennamine hydrochlonde.
solubility, 342
structure 332
Tnphcnylmethane dyes, 356 357
incompalibiLty, 361 362
Index 579
Tnsodium salt, stnictnre, 361
Tntiated water injection (H*0),
554
Tnturalion(s) , of potent drugs, 98
use in homeopathy, 389
Tuamine, solubility, 342
structure, 332
Tvibe(s), colon, 420, 423
duodenal, 423
rectal, 420, 423
stomach, 422*423
Tubing, rubber, 421-422
Tussar Syrup, 175
Tyrothncin, 37!
Tyzine Nasal Solution, 175
Ucon, 260
Ultrasonic therapy, 467
Ultraviolet rays, effects, 467-468
lamps, 468*469
radiation, 465, 467
dangers, 470
therapy, technic, 469-470
Undetpads disposable, 460
United States Atonuc Energy
Comoussion, 556
Untied Slates Dispensatory, infor-
mation on dosage forms, 66
Urdang, George, 1, 2
Unnals, 430
rubber, 414
UJT , Latin titles omitted, 9
Xin, Latin titles listed second
to English, 9
n Valderaldehyde, solubihn, 313
Valenc acid, solubility, 317
van’t Hoff equation, 151
Vaporizer huimdiffers, 432-434
Veegum, 187-188
Veterinary medicine, 393 398
data (1962) concerning, 394
development of profession, 393
education, medical, 393
licensure, medical, 393 394
pharmaceutical preparations
used, farm animals, 395
pets, 395 398
pharmaceutical services re
quired in, 394 395
practiUoners, fieldsof work, 394
Viscosity, adjustment, ophthalmic
solutions, 174
Viscosity — (Continued)
of dispersion medium, stabiliza
bon of su^icnsion by lo
crease of, 182 183
effect of ffi^ylceUulose on ab-
sorption rate of sali^late so-
lubons in rats, 70-71
in emulsions, 189
enhancing agents, inclusion in
solubons, 70
Vilaimn(3), 371-378
A, 372
adsorption on insoluble dilu-
ents, 72
p-aimnobenzoic acid (PABA).
374
anttbenben. 377-378
antibemorrhagic, 373
antineuntic. 377 378
antirachiuc. 372
anuzerophthalmia, 372
ascorbic acid, 374
B, 377-378
B2, 376 377
Be. 376
Bi2. 44. 378
intestinal absorption, 42
biobn, 374 375
C, 374
choline, 375
D, 372 373
Dj, 372
Ds, 372
m dentistry, 386-387
E, 373
fat soluble, 372 373
flavorug, 1^
folic acid, 375
G, 376-377
H, 374-375
heuiattaic. 397
mosilol, 375
K,373
A'l, 37S
Kz. 373
menadione sodium bisulfite,
373
mulbple, in aerosols. 282
nicobnamide, 375 376
nicoUmc acid. 375 376
pantothemc aad, 376
pyndoxine, 376
nboflavm, 376-377
thiamine bydrocblonde, 377-
378
Vitamin(s) — (Continued)
water soluble, 374 378
Volabhty, of solids, 109-110
Warfann, 37
Wanng Blendor with polytron
assembly, 181
Water, solubility of salts in, 292
Water bottles, 409-410
Water number, 213 214
Weighing, 19 22
Aliquot method, 20-22
balance, 19 20
sensibili^ reciprocal of, 20
sensibviiy of, 19-20
Weight of pabent as factor m
calculating dosage, 17
White Lobon, 182
White ointment, as oleaginous
base, 210-211
Williams R T, 44
Wool fat. See Lanolin, anhydrous
Wurster air suspension coabng
process for granules, powders
and tablets, 135
Year Book of Drug Therapy, in
formation on dosage forms, 86
Yellow AB, renstaoee to condt
lions lofluencmg color sta-
bility, 359
solubility, 358
structure. 354, 357
Yellow OB, resutance to condi
boos influencing color $ta
bihty, 359
solubility, 358
structure, 354
Yellow oiobnent, as oleaginous
base, 210-211
Young’s Rule for calculabng dos-
age, 17
Zephiran (^onde See Benzal
komum chlonde
Zinc, 296 299
cUonde, 297
hydration, 296 298
hydroxide, 296
uicompabbilities, 296 299
salts, 296*298
sulfides, 298
Zugich system for determmiog
drug charges, 512
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